In the season premiere, Sam, Dean and John have been left for dead after the Demon plowed a truck into the Impala. Now, as one of the Winchesters hovers between life and death, the surviving family members must face an old and powerful adversary.

After listening to a message on John's (JEFFREY DEAN MORGAN) cell phone from a woman named Ellen (SAMANTHA FERRIS), Sam and Dean decide to track her down. They discover that Ellen runs a roadhouse that also serves as a gathering place for hunters like themselves. Meanwhile, at a small town carnival, a clown is persuading children to let him into their home so he can murder their parents.

When Sam and Dean encounter Gordon (STERLING K. BROWN), a fellow demon hunter systematically killing vampires in a small town, Dean immediately bonds with him. After Sam meets with the lead vampire, Lenore (Amber Benson - "Buffy the Vampire Slayer"), and discovers they are peaceful creatures who survive on cattle blood, he realizes not all supernatural beings are evil and tries to convince Dean.

Dean and Sam investigate the murder of a college student who has come back from the dead seeking revenge on those who mistreated her while she was alive. When confronted, the ghost savagely attacks Sam, leaving him injured. While in town, the brothers visit their mother's grave to pass along something from their father.

Sam and Dean meet Andy, a slacker with psychic powers of persuasion that he uses to gain favors from people. When Andy's friends start dying, the brothers think Andy may be using his powers to kill. Also, after learning that Andy's family was visited by the Demon 22 years ago, Sam wonders if Andy is part of the group of children the Demon told him about—and if Sam will eventually turn evil.

Sam and Dean investigate the brutal slayings of blonde women from the same apartment building and discover that the demon responsible is the ghost of the country's first serial murderer, H. H. Holmes. Meanwhile, roadhouse owner Ellen orders her daughter, Jo, not to follow the Winchesters on their hunt, but Jo defies her and ends up getting captured by the ghost and buried alive.

Sam and Dean investigate the murders of a lawyer and his wife who, right before they died, claimed to have seen a ghost. Before the brothers are able to find the ghost, local detectives uncover the Winchesters' records and arrest them for a double homicide. When the ghost begins to visit Ballard, she wonders if Sam and Dean really are telling the truth—and if she might be the next to die.

Sam and Dean investigate a local bar and discover that it sits upon a site where a deal-making demon has been making people's dreams come true in exchange for their souls. Dean summons the demon to exorcise it but is horrified after it reveals the painful truth about his father's death and tempts Dean by offering him the one thing he wants more than anything—his father.

When Sam has a vision of Dean killing a young man who seems to be possessed by a demon, the two brothers head to Oregon to search for answers. They come across a town contaminated by a deadly virus that drives people to kill. Sam becomes infected and prepares for his deadly fate, but after nothing happens to Sam, Dean decides to reveal what the boys' dying father whispered to him.

After Dean tells Sam what their father told him before he died, the distraught Sam sneaks off to Indiana alone. While there, Sam encounters Ava (KATHARINE ISABELLE), a psychic who admits that she sought Sam in order to warn him of his impending death. Dean discovers that vampire hunter Gordon, whom they have dealt with before, is after Sam and races to find his brother in time to save him.

Sam and Dean investigate two strange deaths at a small Connecticut inn run by a single mom whose young daughter plays with an imaginary friend. The brothers find evidence of voodoo around the inn, and they soon realize that the little girl's imaginary friend may in fact be a demon who is killing the townspeople.

Sam and Dean investigate a string of robberies with a disturbing pattern: In each incident, a trusted employee holds up a bank and then commits suicide. When autopsy reports show the employees' actual time of death as several days before the robberies, Sam and Dean realize that a shape-shifter they have encountered before has returned.

Sam and Dean investigate the murders of several people by individuals who claim they were visited by an angel and were carrying out God's will. After the brothers learn that the victims actually were secretly guilty of crimes, Sam begins to believe the angel really does exist. But Dean maintains his stance that a demon is behind the slayings—until he sees something even he can't explain.

After receiving a frantic call from Sam, who has been missing for over a week, Dean races to his brother's side. He finds Sam covered in blood but unable to remember anything that happened. Upon further investigation, the brothers are horrified to discover a tape that shows Sam killing another hunter in cold blood, causing Sam to believe that his evil side is finally taking over.

Sam and Dean call upon their family friend and fellow hunter Bobby (recurring guest star JIM BEAVER) for help after they are stumped by violent and inexplicable happenings on a local college campus. Bobby arrives with a suspicion as to the culprit behind the killing spree—and the brothers' escalating feud.

While driving down a deserted road, Sam and Dean are startled when a bloody woman, Molly (TRICIA HELFER - "Battlestar Galactica"), bolts in front of the Impala, screaming for help from the crazy farmer chasing her. After investigating, Sam and Dean discover that the man is actually an angry spirit that kills one person at the same time every year and has decided Molly will be his next victim.

While investigating the death of a lawyer who appeared to have been killed by a wild animal, Sam and Dean realize they are actually tracking a werewolf. When it seems as if the lawyer's secretary, Madison, will be the werewolf's next victim, Sam—immediately attracted to Madison—offers to stay overnight to protect her. Dean heads out to hunt the animal and is stunned by what he finds.

Sam and Dean travel to Hollywood to investigate the death of an actor on a horror film set, after rumors spread that he was killed by a ghost. They discover the death was a publicity hoax, but when the executive producer and a studio executive really are killed, Sam and Dean realize they are dealing with a haunted set. GARY COLE guest stars as Brad Redding, one of the stars of the horror film.

After hearing about a ghost that has been killing off inmates one by one, Sam and Dean decide the best way to investigate is from the inside—so they allow themselves to be thrown into a state penitentiary. However, after FBI Agent Henricksen (C. MALIK WHITFIELD) arrives to take over the case, getting out of prison becomes a bigger challenge for the brothers than finding the spirit.

While hunting a djinn, or genie, Dean is attacked and transported to an alternate world. There, his mother, Mary, is alive; Sam is in law school and engaged to Jessica; and Dean lives a very normal life with his girlfriend, Carmen. Dean must decide whether he wants to stay in this safe, new life where everyone he loves is alive—or if he wants to return to the hunt.

Sam is abducted by the yellow-eyed demon and finds himself in a ghost town with children who have special abilities. They learn that the demon brought them together to initiate his endgame: an all-out war against the human race. To encourage Sam to fight, the demon shows him what really happened to one of his parents. Dean enlists fellow hunter Bobby to help find Sam before the battle begins.

While dealing with the aftermath of the fight between Sam and Jake (recurring guest star ALDIS HODGE), one of the powerful people from the ghost town, Dean pays a steep price for his involvement. The demon and his spirits threaten to overtake the hunters—until they receive help from an unexpected ally. Recurring guest star JEFFREY DEAN MORGAN appears as John Winchester.