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.

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.

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.

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

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.

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.