The story starts off in 2010 London, with young Alexis starting her journey from London to Crete. She seeks to learn about her roots, which her mother Sofia has been reluctant to share.

Eleni and young Dimitris reach the island, the place in which they are condemned to live for the rest of their lives. Their exile to the island as well as being away from their families becomes unbearable. To make matters worse, the island suffers from lack of water, something that makes the everyday lives of the lepers even more difficult. Just an association with their illness isolates Giorgos from his fellow villagers, and forces Dimitri's family to abandon their house and move away. Even though Giorgos is one of the few allowed to visit the island to transport goods, he does not find the strength/courage to meet with Eleni for days after.

Giorgos tries to fall into the routine of primarily caring for his daughters, but meets difficulties with Anna's wayward/rebellious character. On Spinalonga, Dimitris makes new friends; The malice schoolteacher of the island, Ms. Kroustalaki, abuses the children, pushing Eleni to decide to teach Dimitri at her own house, with other students also joining later. This causes a clash with the school teacher of the island, who thinks she is after her job and vows to destroy her. Meanwhile, three dangerous long-term convicts are sent by the government to the island in order to patrol the lepers, and Giorgos tells Eleni to be careful so that the convicts will not harm her. At the same time, the water reservoirs on Spinalonga dry up, so Giorgos transports drinking water from Plaka for the lepers to meet basic medical needs. The citizens are also concerned of further new arrivals to the island.

The island receives newcomers from Athens. Their arrival however, is met with resistance from certain residents. Pestered and tortured, the newcomers find help in Eleni, Dr. Lapakis, and president Kontomari amongst others. The shortage of water and the fear of what is to come agitates and scares everyone making matters worse. Across in Plaka, Giorgos forbids Maria from going with him to visit her mother as it is forbidden. Despite this, she hatches a plan to hide on her fathers boat just to get a glimpse of her mother. Meanwhile, the baker Evgenia finds a skin lesson on her neck that will forever change her life. On the island, the newcomers begin to use their knowledge and skills to help better serve the community after recovering from their long journey. But this does not change the opinions of certain residents about them, who are ready to get violent on the island. Just as a big fight is about to erupt, it finally starts to rain much to the joy of everyone on the island.

Evgenia's health becomes worse day by day, and she is haunted by the fear that she may make her children sick as well. She finds refuge at the monastery, where the clergyman convinces her to leave for Spinalonga. On Spinalonga, optimism for a better life is fueled by Nikos Papadimitriou. Elections are held with the active Papadimitriou winning and becoming the new head of the island, but not without a fight from an opposing figure; Kroustalaki receives complaints from parents over her abuse to the children. Anna falls ill with mysterious skin lesions on her body, forcing Giorgos to notify Dr. Lapaki fearing the worst.

War breaks out in Europe; Eleni is named the new schoolteacher by the new head of Spinalonga, angering Ms. Kroustalaki. Dr. Kiritsis visits Spinalonga, bringing hope of a new medicine but also revealing that research for it is still in the initial stage. Maria meets him by the seawall in Plaka, and asks him to make her mother better. However, Eleni's health worsens as time progresses; At their house, Evgenia attends to her and Eleni asks her to look after Dimitri if something happens to her. Island resident Nikos Dimitrakis secretly swims across to Plaka to see his wife and his son; His wife begs him to take them with him to Spinalonga. Swimming back to Spinalonga late at night, the guard is looking right toward Dimitrakis direction but is distracted by Dimitri, who throws a rock at him; Dr. Kiritsis is called off to war.

German troops invade Crete and bomb Heraklion. The residents of Plaka feel the ferocity of the intruders first hand, as they occupy the village and enter their homes and seizing their supplies. In an act of heroism, Giorgos saves Manolio from getting shot by the Germans. Antonis joins the Cretan resistance and leaves with his cousin Damiano and three Englishmen for the mountains. On Spinalonga, Papadimitriou has thought ahead and stockpiled food and other supplies for the residents. Nikos, defying the dangers, swims across to Plaka once again in the middle of the night to meet his family. Upon his return, he is spotted by the Germans and shot dead. The illness takes a toll on Eleni and she collapses forcing her to be transported to the hospital. She later dies with Evgenia and Elpida by her side.

The story flash forwards seven years later when the war has just ended. Antonis returns home to Plaka from the guerrilla warfare, and at the urging of his parents and Anna, he gets a job working in the fields of the rich Vandoulakis family. During the celebration of Saints Constantine and Helen, Anna continues flirting with Antonis, leading up to a kiss. However, when rich land owner Andreas Vandoulakis shows up to the celebration, Anna quickly turns her sights towards him. On Spinalonga, a grown Dimitris has become the new school teacher; Papadimitriou shows an interest in Evgenia, but she ignores his advances. Her husband Vasilis back on Plaka, hides the letters she writes to her children. Just a few days until Grigoris, one of the guards, is set to finish his sentence and leave the island, he discovers he has lepercy. Meanwhile, Kalliopi gives birth to a baby girl, and Dr. Lampakis prohibits her from nursing. However, her baby cries non-stop and does not take to other milk, forcing Kalliopi to give in.

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Anna marries Andreas and her life changes in the blink of an eye; Maria and Giorgos visit Anna at the Vandoulakis villa in Neapoli, where Alexandros makes Giorgos a propsoal to go into business together. Giorgos however declines the offer, refusing to abandon his little fishing boat and the life he has become accustomed to. On Spinalonga, police officers arrive to conduct an investigation into the drowning death of Grigori, but the residents of the island standby Papadimitriou. Meanwhile, day by day Papadimitriou and Evgenia grow closer; Evgenia's daughter Athinoula is uneasy with the fact that she has not received contact from her mother, and asks Giorgos if she is well. Secretly from her father, she gives Giorgos a letter to deliver to her mother secretly. Also, Dr. Kiritsis ups the dosage of the experimental medicine to the volunteers, which produce unpleasant side effects.

Evegnia and Papadimitriou grow closer, and he gives Evgenia her daughter's letter; Ilektra's visions worsens almost to the point she can not see anymore. Also, the side effects of the medicine have began to worry Papadimitriou and Dr. Lapaki, but Dr. Kiritsis remains unfazed and asks that they increase the dosage. Meanwhile in Plaka, Pavlos intercepts his daughter Fotini picking up a love letter from Stefanos, and realizes that they have been seeing each other. He prohibits her to see him again, though Stefanos asks for her hand in marriage. Also Dr. Kiritsis makes a house call for Evgenia's children in Plaka, and determines they have contracted leprosy and should be sent to Spinalonga immediately. Evgenia is heartbroken to hear the news.

Evgenia's children arrive on Spinalonga, and their depressed father commits suicide; Ilektra realizes she is slowly losing her sight; Dr. Kiritsis asks to increase volunteers, to which Papadimitriou argues against after witnessing painful consequences. Dr. Kiritsis examines Dimitri, and discovers that he was misdiagnosed with leprosy and actually suffers from psoriasis; Dimitri asks the doctors not to tell anyone. Meanwhile in Neapoli, Andrea's cousin Manolis Vandoulakis makes a surprise visit and charms Anna from the first moment. In Plaka, Stefanos works nonstop in Palvo's taverna seeking to gain approval to wed Fotini. Back on Spinalonga, Papadimitriou is informed of Vasili's suicide, and undertakes the duty of telling Evgenia; Upon hearing the news, Evgenia becomes an emotional wreck and falls into his embrace. Her children witness them holding each other and run away.

Full of guilt, Evgenia searches for her children, but Kroustalki finds them first and scares with bad stories about Papadimitriou; The children return home, but Lefteris refuses to talk to his mother and writes letters to his father. Evgenia asks Papadimitriou to end their relationship. Meanwhile Dr. Lapakis feels guilty about misdiagnosing Dimitris, and tries to convince him to leave the island. He however refuses to leave Ilektra, and asks her to marry him. In the meantime, vaccinations of the experimental drug begin on the second batch of volunteers. Also Stavro and Kallipoi's newborn gets sick, forcing them to take it to the hospital, where they run into Dr. Kiritsis who does not know the truth about the newborn. Back on Plaka, Stefanos continues working hard at Pavlo's taverna, and in Neapoli, Manolis tries hard to charm everyone.

Dr. Kiritsis discovers that Kalliopi's baby is actually healthy, but decides to keep it on the island to perform scientific research instead of sending it for adoption. Dr Kiritsis also begins mixing medicines in an effort to find a cure, which result in deaths with Papdimitriou demanding he stop immediately, threatening to send a letter to the government. Meanwhile, Dimitris tries to get through to Lefteris who remains isolated, and becomes even more so when he learns of his father's death. In Neapoli, Alexandros gives Manolis some responsibilities and powers, and he charms and is charmed by Anna more and more each day; Antonis sees Manolis going in and out of the house when Andreas is absent, and suspects something is going on between Manolis and Anna. Anna invites her father and Maria to the house for his name day, where Manolis becomes impressed by Maria. Anna realizes this, and becomes incredibly jealous.

Manolis and Antonis plan a gathering in Plaka; Foteini picks up on Manoli's attraction to Maria, but Maria appears unfazed. Manolis speaks of Maria with enthusiasm, and Anna tries to hide her jealousy toward her sister. Meanwhile on Spinalonga, Lefteris continues to hold his mother responsible for his fathers death, and Papadimitriou confronts Dr. Kiritsis about the side effects of the drug trials and warns him to stop once again. Volunteers continue to dwindle as the side effects turn deadly, until a letter finally comes from the government ordering Dr. Kiritsis to leave the island and stop the experimental drug trials. Also Stavros and Kalliopi are found at an impasse and escape from the island with their daughter and with Dimitri's help.

Papadimitriou raises black flags on the walls and gates of the island, declaring a hunger strike and commercial embargo between the island and the mainland in an attempt to pressure the government into reinstating cut benefits; the plan is met with resistance from his opponents and residents who suffer the consequences. The residents of Plaka are also found in a very difficult situation since most of the town live off of the commercial trade with Spinalonga. The government sends representatives to the island in an attempt to convince them to stop the embargo, but Papadimitriou will not budge and the government decides to reinstate their benefits bringing an end to the strike and embargo. Meanwhile Evgenia becomes heavily ill and in desperation Lefteris asks Papadimitriou for help. Also Dimitris reveals to Ilektra that he is not sick with Leprosy but still wants to remain on the island, and she tries to commit suicide thinking she is the reason keeping him from leaving the island. Back on Plaka Manolis continues to visit often, showing his interest in Maria, until he finally asks her father for her hand in marriage.

Papadimitriou approaches Evegnia's children and asks Lefteris to work at the island's newspaper; Evgenia becomes happy seeing her children begin to like him. Meanwhile Manolis announces to his family that he has proposed to Maria, and Anna hides her jealously pretending to be happy for her sister. Giorgos is ecstatic at his daughter's good luck, and Manolis and Maria have an engagement celebration in Plaka. Anna does not attend the celebration due to her jealousy, instead pretending to be sick. Later Anna visits Plaka for the first time in a long time where Maria is preparing for her wedding and marriage, but Maria discovers marks on her leg that resemble those of her mother's; Anna sees them as well.

Lefteris begins to like Papadimitriou and understands that his mother loves him and wants them to live together. He tells his mother he wouldn't mind living at Papadimitriou's house, and the family moves to his house. Meanwhile Giorgos and Maria visit Dr. Kiritsis in Heraklion for examinations, where Dr. Kiritsis diagnoses Maria with leprosy and informs her she must be sent to Spinalonga. A crushed Giorgos tells Manoli the news, and Anna reveals to the Vandoulakis family that her mother also suffered from leprosy like her sister, and that she had lied to them about her cause of death being from a heart attack. Alexandros reacts with rage to the news, and orders Anna to leave his house immediately although Andreas and his mother do not approve. He also turns away Giorgos, shouting slurs at him and telling him that they fooled and embarrassed his family. Alexandros orders Andreas to get a doctor to examine Anna. Also Manolis bids farewell to Maria, telling her that whatever they had is over; Maria leaves Plaka for Spinalonga.

Maria arrives in Spinalonga and settles into the house where her mother lived and died. On the island she meets her mother's old friend Elpida, which she knew about through her mother's letters to her as a child, as well as Dimitri which Eleni raised like her own child, and her enemy Kroustalaki who says bad things about her mother to her. In Plaka, Savina tries to comfort Giorgos, and he continues to visits his daughter at the port on Spinalonga like he used to meet his wife. In Neapoli, Anna has locked herself in her room all day, and the Vandoulakis family brings a doctor to examine her for leprosy. Meanwhile Manolis has been missing for days. Also Dr. Kiritsis makes a sudden return to Spinalonga, arriving with good news from America on the progress of research for a treatment. Despite the good news, Papadimitriou demands he leave immediately. Meanwhile Maria falls into a routine on the island, being offered a role in a theater production despite her initial refusal. Later the daughter of a mayor from a different nearby village is diagnosed with leprosy, and a mob headed by the enraged mayor from the village forms in Plaka with intentions to cross over to Spinalonga and burn the island down.

Dr. Kiritsis manages to stop the mob threatened to burn the island. The people of Spinalonga welcome him as a savior. However, his efforts to convince the people and the president Papadimitriou for providing the new drugs meet their incredulity iven the previous failure of the promin drug. Meanwhile, Dr. Kyritsis begins visits to Maria's house. Manolis returns to Neapoli to convince Anna to apologize to her father in law. Andreas asks Manolis to go with his wife in Plaka to see her father. On the way they detour.

Giorgos visits for the first time the interior of the island and the home of his daughter, Maria. The same house where his wife Eleni lived and died. Elpida, which participates in the new experimental treatment, dies. Dr. Kiritsis tries to convince Papadimitriou and the sorority members to volunteer in the new drug to set an example to the others. The results of the new drug seem promising. Maria asks to volunteer. Kroustalaki sees Dr. Kyritsis visiting Maria's house and pours poison for another time. In Neapoli, Antonis understands the love affair of Anna and Manolis. Anna announces to the Vandoulakis family that she is pregnant.

The time passes and in Neapoli, Anna baptize her daughter with Manolis being the godfather. Manolis avoids Anna which shows more passionate than ever. Alexandros Vandoulakis proposes to his nephew to inherit a large part of their family estate in Messara and to leave Neapoli to attent the estate. Anna feels trapped. Alexis realizes for the first time that her mother, Sophia, is the daughter of Anna. She asks the elder Fotini, if the father of her mother and grandfather is Andreas or Manolis. The relationship between Maria and Dr. Kiritsis becomes more familiar but both have reasons to hesitate and fear to make dreams for the future. At Spinalonga the first four patients are cured.

Manolis is leaving to take over the estates of his uncle in Messara. Anna loses all hope but rejoices when her husband tells her to go together to visit him. Eventually, Andreas goes by himself and finds his cousin. Anna can not contain her frustration in front of her in-laws and argues with her husband when he returns from Manolis. In Spinalonga many people are hesitant to leave because they do not know how to greet the outside world after so many years. They decide to leave the island all together on 25 August. The people of Plaka prepare for them a great feast. Anna and Andreas are preparing to go to Plaka to greet Maria.

The people of Spinalonga arrive at Plaka. The people of Plaka welcome them with emotion and joy. The disease was defeated! The fights and struggles of doctors and patients are rewarded... The party goes on. The marriage proposal to Maria from Dr. Kyritsis makes the happiness of both greater. Anna and her husband, reaching Plaka, squabble. Τhe last act of a drama will take place there, where perpetrator and victim blinded by their passion will close every door to logic and set their fates and that of their families. The Vandoulaki family dissolves... Maria, once again, aside her own desires to be with her ​​father, who is so tortured... The love of Dr. Kyritsis, however, is very strong and persistent... Maybe they both have the opportunity to pursuit happiness together...