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 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.

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.

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.

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.