While continuing his quest to figure out who he is and from where he came, John Doe must use all his unique abilities to solve a gruesome murder case, initiated when a seemingly innocent individual dives into a swimming pool which he discovers is filled with human blood. Meanwhile, Lt. Jamie Avery, impressed with Doe's ability to help the police with the case, attempts to surreptitiously learn his real identity. Karen is fired from her waitress job at The Sea and convinces Doe that he needs her as his assistant. Also, a mysterious woman may have information on Doe's identity.

A woman, Paulette, picks up a locked case and has it stolen, then comes to John for help. Moretti, a dead scientist, developed chips to augment the human brain and left them to her. John accepts, believing chip-augmented brain processes may be connected to him. The trail leads to Moretti's house and a dead man — the thief, then to a on-line escort service where it turns out Paulette works. John figures out Paulette has the key on her charm bracelet and opens the case — it has a motherboard set up like a map of the city, and John and Paulette track the location to an abandoned basement being used as a lab with comatose accident victims being used as subjects in the chip experiments. Then they figure out the case contents have bar codes but when John scans them for info a hacker starts blowing up city sites through the electrical and water system and demands the case be given to him. John takes the case and tracks the hacker back to a nearby mall — it's Moretti's assistant Johansen...

John is hit by lightning on his chest-brand and can see in color — going to see a fresh body, John realizes he's also lost access to his vast supply of knowledge and all the physical talents it provided. It's not a good time as a killer strikes, leaving a kidney from his victim with the promise of more to come. The killer strikes again with two killings as John tries to come to terms with his newfound ignorance and the loss of his money when he can't call the shots for his broker. John is bitter and reluctant to admit his newfound loss to anyone, and a disappointed killer threatens to come after him. It turns out that two women, sisters, are working as the killers and lure John into a trap — fortunately John figured the killer(s) were women and he'd be targeted and the police have him wired and are watching. While pursuing one of the killers John is hit with electricity again and is back to being color-blind and super-smart.

When skeletal remains are found at a construction site, the ownership is traced to a man who is a dead ringer for John.

Doe suspects a link to his own identity when a naked man with a similar brand and no recollection of who he is washes ashore from Horseshoe Island, similar to Doe's arrival in town.

John copes with his first nightmare over Karen's death while helping the police in the deaths of several young girls. A psychic, Delphine, helps them locate two of the bodies in a nearby park. John is skeptical of her abilities but begins to believe she has some gift when she sees a presence and a darkness about him. After the third girl turns up dead, Delphine leads them back to the park where they find a skeleton from five years earlier . . . around the time she started blacking out and her gift started manifesting. John determines that Delphine survived the killer's attack and suffered amnesia, thus explaining her "psychic" connection to the killings and the park. John soon determines all the victims worked in food services, and that a butcher, Jeb Crosby, is the killer . . .but not before he captures Delphine. John and the police arrive just in time to save her and John comes to terms with his guilt over Karen's death.

Ken Rothman, an ex-police officer that Avery got fired for beating a suspect, gets into the police HQ by faking his death and he and his men quickly take the station and most of the staff (except Frank) hostage. Rothman demands his reputation be cleared, but John manages to get free and escape into the building, and soon discovers Rothman has a supply of Russian-made smallpox. John manages to take out a few terrorists before being recaptured and Rothman leaves John and Avery behind with a shattered vial of smallpox. It's fake, but the whole thing is a ploy to get hold of smallpox vaccine to sell as a bio-weapon. Doe figures it out and they capture Rothman just in time.

Victims turn up cut in half and the police call in John. DNA leads to a suspect locked up in an asylum who claims he can leave the place in dreams. John tracks the man's twin brother, actually a transsexual, and after another victim turns up he concludes that the twins were separated at birth and the victims are the child-service officials who had them separated and their mother is the one taking revenge. Meanwhile, after hypno-regression therapy fails, John tries dating which doesn't go over well. After a brief sensory-deprivation session with the asylum doctor, Jansen, John has some vague visions but Jansen disappears along with the session tape. The police believe the same killer disposed of Jansen, but we find out he's been killed by the mysterious woman we saw at the end of the previous episode.

The mysterious symbol on Doe's chest is part of the calling card left by a serial killer known as The Mourner who knows a lot about Doe, whom he challenges with cryptic clues as he puts more lives in danger.

When a young Seattle DJ is mysteriously murdered by a seemingly non-existent perpetrator, Doe helps unravel the enigma while pursuing a relationship with Rachel Pembroke (from 'Manifest Destiny').

Investigating a violent and seemingly impossible crime committed at the Seattle Museum of Art, John discovers that Karen is involved.

When a young boy Wesley and his mother approach John Doe claiming that sperm bank records indicate he is the boy's father, John is pulled into a mystery as he tries to track down the list of donors and finds two of them dead, their brains removed.

The case of a mysteriously kidnapped teenage girl sends John Doe and Det. Frank Hayes on a frantic investigation to save her before it is too late.

Returning from Karen's art show, John thwarts a bomb threat but it's a ruse for the mysterious group that's been plaguing John to grab Karen. The group thinks John knows something about a staff with a phoenix on it and Karen may know it as well. The trail leads to a warehouse full of dead deaf people and then John gets snatched by the NSA. They want to know about "Phoenix" but John doesn't have a clue and the head guy, Sam, lets him go eventually. Karen manages to call John long enough to give him a clue leading him to . . . Horseshoe Island. Phoenix has evacuated it after an extensive excavating operation, leaving Karen's corpse behind. The gang bury Karen and decorate her building with her last painting. But the mystery isn't quite over — John gets a report that "Yellow Teeth" is barely alive — he visits her and she warns that Phoenix is seeking a staff tied into his destiny and they won't stop coming until they get it. She dies, and the audience sees the staff is in the Vatican.

High school kids are surprised by a bright light in the forest and an astronaut who walks toward them that they shoot. The police and John investigate and determine the astronaut actually died of a lack of oxygen resulting in cyanosis but a Colonel Dunagan moves in and take the body — John taps into satellite photography and sees a blast pattern that matches the one on Horseshoe Island that accompanied his arrival. John, Digger, and Frank sneak into the woods to examine the site and find a large pod. The pod is a Mars environmental test system and inside the trashed interior are a bunch of astronauts dead just like the first astronaut — then they get sealed in. Meanwhile Avery pursues her own investigation despite the military government and after interviewing Dunagan's staff sergeant, believes Dunagan is involved. The men start sniping at each other due to cyanosis symptoms while Stella and Avery track them down. John uses its navigation beacon to send out a SOS. The Staff Sergeant is...

A man escapes from the Seneca Institute and is run over — Digger recognizes him as his blood brother Jay Dougan and John can see Dougan's picture in color. The two of them travel to Northam where the color leaves the dead man as John watches and the body has teeth with no enamel and a tag-id on his tongue. The two of them find the man's Army medal in the woods and follow it back to the Institute where mental patients are kept, but there's no evidence Dugan was ever there. They sneak in and John witnesses patients being drugged to act as "remote viewers", seeing things psionically from a distance. John sees one blind patient, Michael, in color and playing "My Funny Valentine" and gets him out — he has scrambled senses and says he was told he was suffering from a fatal brain disease (similar to John's history — see "The Mourner".) and they took him in and help him develop his gift to see at a distance along with other orphans and homeless people. They realize they're being watched by Sam...

Lenny renews his duel of wits with John, kidnapping Lt. Avery and sending a series of cryptic clues with a fatal deadline. A new captain makes things hard for John and he and Digger go off on their own to hunt down the killer. John meets up with Frank and they figure both that the police are on the wrong trail going into a booby trap and where Lenny really is. But Frank accidentally shoots John, killing him and letting Lenny escape. It's a ruse to draw Lenny out at the cemetery with no one in the way, one that (more or less) works. We do find out that Lenny branded himself with John's mark and didn't have any deep connection to him.

John discovers clues that lead to his real life, a trail that takes him to Idaho and raises more questions than answers.

John boards a flight for London but discovers a murder-mystery in mid-air while getting to know a pretty fellow passenger and neurologist.

John awakens to find himself stranded on an island off Seattle. His uncanny abilities are soon apparent to him when he is rescued by Asian fishermen and begins to speak the sailors' language fluently. When he sees a news report about a kidnapped girl, the color-blind Doe realizes that he is seeing the child in color. Sure that she holds the key to the mystery of who he is, Doe is eager to find her and offers his assistance to the skeptical police.

John begins to experience an onslaught of bizarre visions and images then blacks out — the visions lead him to a faceless murder victim and a cannery where the Phoenix Organization and the remote viewers were situated. John meets Sam of the NSA (the murdered man is one of Sam's undercover agents) and they manage to capture the Trenchcoat Man and discovers he's not deaf and speaks fluently in Sanskrit and Latin. Trenchcoat hints at John's destiny, how he's one of them, and that Michael (from "Remote Control") may still be alive and a key to the mystery – then he escapes using strange mental abilities of his own. Sam introduces John as a "Class 1" to Lucas Doya, the founder of the U.S.'s own remote viewer program through the DoD — Doya puts John through a series of tests to heighten his own remote abilities and John locks on to Teresa in a copper mine. The NSA, Avery, and Frank close in with John as the remote viewers get a vision of the location of the Staff (from "Ashes to Ashes") in ...