Kara and Alex head home to Midvale for a little R&R. While there, Kara recalls a painful memory of a childhood friend's death and how that traumatic experience brought the Danver sisters closer together.

When a new threat emerges in National City, Kara/Supergirl teams up with her cousin, Clark Kent/Superman, to stop it. Kara is thrilled to have family in town but it leaves Alex feeling a bit left out. Meanwhile, Hank and Supergirl are stunned by the pod that came crashing to Earth.

As Alex searches for Jeremiah and Kara investigates a series of alien kidnappings, the sisters realize they must break the rules to foil a new Cadmus plot. In an effort to get Snapper Carr to run a story that would help her stop Cadmus, Kara agrees to set up an interview between Snapper and Supergirl.

When multiple children get sick from lead poisoning, Morgan Edge points the finger at Lena and blames her creation of the lead bomb she made to save National City from the Daxamites. While Lena knows she never intended any harm, she fears there may have been a flaw in her design, leaving her responsible. Kara teams up with Samantha to clear Lena’s name, but it turns out to be harder than they thought. Meanwhile, Alex and Maggie make a crucial decision about the future of their relationship.

When Winn and the team discover an alien ship has crash landed deep underwater beneath National City, Kara/Supergirl is called in to investigate. Meanwhile, Hank attempts to bond with his father, Myr'nn. Samantha, eager for some understanding of the changes she has been experiencing, looks to her estranged mother, Patricia Arias, for answers.

Someone tries to kill Morgan Edge and he barely survives. He accuses Lena of being behind the attempt and vows to destroy her. When Lena fears her hatred for Morgan will take her to the Luthor dark side, Kara steps in to help her friend. Meanwhile, after Sam realizes she’s losing time, she confides in Alex who decides to run some medical tests to see if she can find out what’s going on with her new friend.

In the wake of Lex Luthor's return, the show flashes back to what he's been doing for the last two years and how his secret machinations and plans have affected Supergirl and Lena.

Kara turns on her friends and the citizens of National City after being exposed to Red Kryptonite makes her malicious and dangerous. Also, Cat appears on THE TALK to discuss Supergirl.

Kara gains a new ally when the lightning-fast superhero The Flash suddenly appears from an alternate universe and helps Kara battle Siobhan, aka Silver Banshee, and Livewire in exchange for her help in finding a way to return him home.

An attack is made on the President as hot-button, alien vs. human rights issues heat up in National City. Supergirl and the DEO are assigned to protect the President and bring in the responsible party. Alex teams up with Detective Maggie Sawyer to investigate the case while Kara searches for a recently escaped Mon-El, who she fears may be the alien behind the assault.

Armek, a White Martian, descends on National City intent on taking M’gann back to Mars to face her punishment as a traitor. Hank and Supergirl determine the best way to keep M’gann safe is to bring her to the DEO. However, when it is revealed that Armek shape-shifted into M’gann and is now loose in the building, the team realize he could be disguised as any one of them.

When Jeremiah Danvers is rescued from Cadmus, Alex and Kara are thrilled to have their father back. The Danvers arrange a family dinner to celebrate but things go awry when a suspicious Mon-El starts to question Jeremiah about his sudden return.

Supergirl challenges Rhea to battle to save National City. Meanwhile, Superman returns and Cat Grant offers Supergirl some sage advice.

Kara’s friends must find a way to save her life when a parasitic alien attaches itself to her and traps her in a dream world where her family is alive and her home planet was never destroyed. Also, Alex, Hank and the DEO must fend off a Kryptonian attack while Kara is out of commission.

Psi, a thief with psychic powers, attacks National City. Able to immobilize people by tapping into their worst fears, Psi proves a formidable opponent for Supergirl. Meanwhile, James and Lena are at an impasse, and Samantha starts her new job at L-Corp.

As Reign continues to terrorize the city, Supergirl teams up with Saturn Girl, and the two recruit Supergirl’s former enemies, Livewire and Psi, to form a team for a mission to Fort Rozz to recover a prisoner who has information on how to defeat Reign once and for all. Meanwhile, Alex babysits Ruby.

The DEO captures a second Worldkiller, Purity. Supergirl and Alex use very different methods of interrogation with Purity in the hopes of finding out how to defeat Reign. However, Purity escapes and attacks the city’s subway tunnels. Meanwhile, J’onn, Winn and Mon-El band together to fix the Legion ship.

Myr'nn inadvertently causes psychic disturbances at the DEO; Supergirl must work with J'onn to contain the chaos; Mon-El begins training Kara in fighting techniques he's learned in the future.

Kara and her friends must rely on their inner strength and courage when an earthquake strikes National City. Also, Alex’s mistrust of Hank reaches a breaking point when the earthquake traps them in the DEO with Jemm, a powerful alien escapee.

J'onn J'onzz reveals the details of meeting Kara and Alex's father, Dr. Jeremiah Danvers, and assuming Hank Henshaw's identity. Also, Kara debates trusting someone new with her secret identity and Siobhan plots against Kara.

Lena’s ex-boyfriend, Jack Spheer, comes to National City to unveil his big breakthrough in nano-technology, which has the potential to eradicate all diseases. Lena asks Kara to attend Jack’s conference with her for support. When Kara sees Snapper in attendance she’s inspired to tap back into her reporter skills and questions Jack on his discovery, which ultimately leads to a bigger investigation that puts everyone in danger.

Supergirl grapples with whether or not to obey the President's orders regarding Rhea's latest actions. Meanwhile, Cat Grant returns to National City.

Barry and Iris’s wedding brings the gang together, but things go awry when villains from Earth-X attack the ceremony. All of the superheroes band together with help from their super friends like Citizen Cold, The Ray, Felicity Smoak, Iris West and Alex Danvers to take on their most formidable villains yet. Earth’s mightiest heroes – Green Arrow, Supergirl, The Flash and White Canary – lead their teams into battle to save the world. The crossover continues on Arrow S06E08 Crisis on Earth-X (II), The Flash S04E08 Crisis on Earth-X (III) and DC's Legends of Tomorrow S03E08 Crisis on Earth-X (IV).

Struggling to heal from her injuries inflicted by Reign, Supergirl remains in a dreamlike state, unable to be reached. Mon-El recruits one of the Legion members, Brainiac-5, to try to bring her back. Meanwhile, Reign continues her rampage on the city so the DEO teams up with the Legion of Superheroes to try to stop her.

Kara faces off against her mirror image when Bizarro, a twisted version of Supergirl, sets out to destroy her. Also, Kara grows closer with Cat’s son, Adam.