Despite Dean's directive to forget about looking for a cure for the MOC, Sam continues to do research. Dean suspects Sam is hiding something but decides to focus on a murder case where they run into Cole.
Sam and Dean listen to a message on John's cell phone from a woman named Ellen (guest star Samantha Ferris)and decide to track her down. They are shocked to discover Ellen runs a road house that also serves as a gathering place for hunters like themselves. Meanwhile, at a small town carnival, a demonic clown is persuading children to let them into their home so he can murder their parents.
The Winchester brothers enjoy Dean's new baby: a shiny newly restored car, while checking out a report of two recent human deaths and over a dozen split-open cows in the small town of Red Lodge, Montana. The local sheriff laughs at Sam and Dean's idea that a cult is behind it, claiming it happens naturally in the sun. But when Sam and Dean sneak into the morgue under false pretenses, they find a victim that has retractable vampire fangs. They catch black demon hunter Gordon Walker, who claims to be a friend of their late father and having made both kills after six ...
Sam insists to visit ma Mary's grave, although empty and meaningless to Dean, who is however intrigued in the cemetery by the perfect circle of dead vegetation around the three days old grave of local college student Angela Mason who died in a car accident, suspecting the ground is desecrated, Sam thinks it's another diversion not to have to think about either deceased Winchester parent. Her roommate Lindsey says Angela's grieving boyfriend Matt Harrison just slit his throat, all plants in his place are also dead. Another student, Neil Levine, tells Matt blamed ...
Visions show Sam, still hunting for the master demon with Dean, the way to another small town where paranormal events occur, some innocent, some chillingly evil. The Winchester brothers are convinced it's all the paranormal work of 23 year-old Andy Gallagher, but doubt as that boy, although a bit of an outcast looser living in a van filled with philosophy as well as rock music seems sincerely surprised and using his powers with self-control. Soon they find after rescuing Tracy from what seems his work there is another at least as able and less scrupled, in fact Andy's...
Another one of Sam's visions in which Dean kills a man by name of Duane Tanner sends the Winchesters to Rivergrove, a near ghost town facing mass demonic possession. Sam and Dean begin to believe that the demons are trying to destroy the town from the inside out when the remaining town-folk try to kill them.
Sam is shocked when Dean finally tells him their dad asked him to watch over Sam to save him, or if that fails kill him. Sam leaves alone to let Ash look up a same-type clairvoyant demonic victim. Ava Wilson, from Peoria, Indiana, fits that bill and looks up Sam to warn she saw his death, then leaves ridiculing him. Dean followed Sam, just in time to intervene when crazy Gordon Walker turns up, who will stop at nothing to destroy 'utterly evil' Sam. It's a testing fight for the brothers.
Sam and Dean visit the Pierpont Inn, a creepy old mansion turned failing hotel. They meet the owner, Susan, and her daughter Tyler, who are packing to move after they sell the hotel. Tyler is playing with a little girl named Maggie. The brothers notice strange items around the hotel, including an urn with a familiar pattern, dolls with their heads backwards and Susan's mother, who looks vacant and beyond terrified. When Susan finds them in her mother's room trying to talk to her, she throws them out and threatens to call the cops.
A jewelery store heist committed by an employee is linked to a mysterious bank robberies bring Sam and Dean into the chase. The weird part seems to be the fact that the suspects end up dead before even getting their hands on the money. A friendly tip points towards another shapeshifter. However, the search is interrupted by a hostage crisis.
In Providence, Rhode Island, the local Gloria kills a man claiming that an angel in a beautiful white night had chosen her for redemption and asked her to stab the sinner to accomplish God's will. Dean and Sam investigate the case and they discover that other people had been visited by the angel and committed murders. Further, the angel has appeared after the death of Father Gregory, who was murdered on the steps of his church two months ago. When Sam is visited by the angel and asked to kill a man, the skeptical and atheist Dean confronts the faith of Sam telling ...
After Sam goes missing for over a week, Dean finally receives a phone call from his brother. Dean finds Sam in a hotel room, covered in blood and suffering from the effects of a week long memory blackout. Upon investigation, the brothers find a video-tape of Sam killing another hunter in cold blood, which leads Sam to believe his dark side is taking over. When the dark side finally emerges Sam attacks Dean and continues on his hunter killing spree with his next targets being family friends Jo Harvelle and Bobby Singer.
Sam, Dean, and Bobby encounter what appears to be a dancing alien, a chainsaw killer, alligators in the sewers, and other oddities straight out of the tabloids while probing strange occurrences on a college campus. They discover all are actually the work of one college janitor, a Trickster who has the ability to conjure into reality anything he wants. Not helping matters is the brothers' slowly escalating feud which Bobby suspects is also the work of the Trickster.
Molly and her husband are driving along a long deserted highway at night when they come upon a farmer. The next thing Molly knows both the husband and the farmer have disappeared. Things get worse when the Winchesters inform Molly that the farmer is actually a highway ghost who, it seems, appears annually to claim a new victim, who happens to be Molly this time.
Sam and Dean come across werewolf activity when they investigate the death of lawyer who was believed to have been killed by a wild animal. While Dean tracks the werewolf on the outside, Sam offers to protect Madison(guest star Emmanuelle Vaugier)who is likely to be the werewolf's next target.
The Winchesters go undercover as PAs on a haunted movie set after getting wind of reports of tag teaming ghosts. The brothers deal with an asinine studio executive out to make cheap marketing stunts(guest star Gary Cole), a disenfranchised screenwriter seeking revenge for unnecessary revisions to a formally great script, and Dean's fan-boyish feelings for the leading lady.
When an old block is reopened in the Green River County Detention Center after thirty years, a fiend is released, killing the interns. Three months later, Dean and Sam are arrested during a heist to be sent to the haunted prison to help Deacon, a former friend of their father. While FBI Agent Victor Henricksen presses Dean, the public defender Mara Daniels believes the brothers are not guilty of most of the inconsistent charges against them, and helps the Winchester brothers in the end.
Dean gets attacked by a Djinn, a creature capable of warping reality. The next things he knows he's in Lawrence, Kansas, in a stable relationship with a woman named Carmen, his mother is alive and well, and he and Sam are no longer on speaking terms. When the idea of a peaceful existence begins to settle in, visions of his previous life as a hunter start appearing out of nowhere.
The Yellow Eyed Demon transports Sam, Andy, and Ava along with other "Special Children" Jake and Lily to the remains of a ghost town to initiate the first steps of his war against mankind. Dean contacts Bobby Singer, Ash, and Ellen for help in locating his brother.