When the boys stop at a diner, Sam goes to buy food, while Dean muses about pie. Suddenly the radio starts cutting out. Dean rushes into the diner to find Sam gone and the staff and customers dead, and sulfur staining the back door.

Dean goes to Bobby for help, but he has no information on demonic activity across the country. Ringing the Roadhouse, an agitated Ash admits to having information he will only reveal in person.

Sam wakes up to find himself in a deserted town. He runs into Andy, whom he’d previously met when Andy’s twin brother was using his psychic powers to kill people. Together they find Ava who says she has only been there for half an hour even though it is five months since Sam last saw her. Also in the town are Jake Talley, an American soldier whisked away from duty in Afghanistan, and Lily. Lily reveals that her power is that people’s hearts stop when she touches them; Jake’s that he is super strong.

The group is doubtful when Sam explains that a demon is behind things, until an Acheri Demon in the shape of a young girl, attacks Jake. While Sam leads the group to find supplies and weapons, Lily tries to leave the town through the woods, but is killed by the demon. Desperate for Dean’s help, Sam gets Andy to try to send him a vision of where they are.

Dean and Bobby have arrived at Harvelle’s Roadhouse, only to find it burnt out and the occupants, apparently including Ash but not Ellen, dead. Dean is suddenly struck by flashes of images sent by Andy. With Bobby’s help they work out that Sam is in Cold Oak, South Dakota.

Sam has surrounded a room with a salt line, and as they wait for what may come, Sam dozes off. The Yellow-Eyed Demon appears to him, and explains that his plan is for the children with special powers to fight amongst themselves until the strongest is left to lead the Demon’s army. He tells Sam, with his leadership qualities and hunter training, is his favorite. The Demon admits to killing Jessica so Sam would go back to hunting. He then shows Sam a vision of what happened the night Mary died. Sam sees that the Demon fed drops of his blood to baby Sam, and that Mary knew the Demon.

On waking Sam finds that Ava has disappeared, and he and Jake go to look for her. Ava returns to the room, breaks the salt line, and summons an Acheri Demon who kills Andy. When Sam returns and confronts her, she admits that she has spent the last five months developing her powers, and killing the other children who arrived. Just as she summons another demon, Jake kills her.

As Sam and Jake prepare to leave the town, Jake admits he doesn’t trust Sam and attacks him. After a fight, Jake appears to be unconscious. At that moment Dean and Bobby arrive. As Sam walks towards Dean, Jake grabs a knife and stabs him in the back, then runs away. Bobby chases him. Sam collapses into Dean's arms and is unresponsive to Dean's pleas for him not to leave him. As Dean says that it's his job to take care of Sam he sees the truth, that Sam is fatally wounded. Sam spends his final moments cradled in his distraught brother's arms.

Episode - 22 [All Hell Breaks Loose, Part Two] => Season Finale

Sam is dead and Bobby suggests that it's time they bury him and leave to prepare for whatever is to come next. Dean is furious at the idea and tells Bobby to leave.

Meanwhile, the Yellow-Eyed Demon appears to Jake and tells him that he is the strongest and has to do something for him.

Dean is unable to decide what to do next and is heartbroken at the thought of letting everyone in his life down. In a fit of rage, he drives to the nearest crossroads and summons a demon. The demon, however, will not agree to anything. In a last desperate measure, Dean decides he'll agree to anything. The demon offers to bring Sam back and in return offer's Dean one year, and one year only, promising that if he tries to get out of the deal, Sam will drop dead straight away.

Sam wakes up in pain but is fully healed. Unaware that he has been resurrected from the dead, Dean lies and tells Sam he was only wounded. Sam fills Dean in on what happened previously and wants to recommence hunting immediately. Dean, reluctant but unable to deter Sam, drive them over to Bobby's place.

Bobby sees Sam and knows immediately what Dean did but plays along, despite being reproachful. So far Bobby has found nothing but demonic omens appearing in the state of Wyoming, except for one particular area. Ellen appears at Bobby's and, after Bobby gets her to drink Holy Water to confirm that she is not possessed, she produces a map of Wyoming that Ash left. On the map, five locations have been marked with X's. Upon research, the X's each marks an abandoned frontier church, all mid-19th century, built by Samuel Colt. Also built, was a set of iron railway lines connecting each church in the form of a pentagram, forming a hundred squre mile devil's trap.

Within the devil's trap, is an old cowboy cemetery, which Dean suggests could contain something that the Colt wants to prevent from getting out as opposed to demons trying to get in. They know the devil's trap is still unbroken because of the lack of demonic omens in the area and Bobby says that full-blooded demons would not be able to enter. Remembering his dream from last episode, Sam understands the purpose of the Special Children.

Jake arrives Wyoming and the Yellow-Eyed Demon gives him instructions to open a crypt with the Colt as the key. On arrival at the cemetery, Dean, Sam, Bobby and Ellen ambush Jake but are overpowered by his psychic mind control. Jake unlocks the crypt and is shot dead multiple times by Sam. Dean removes the Colt and they dive for cover as the doors are flung open and a tremor ripples out from the crypt, breaking the railway line and thus the devil's trap. Hundreds of demons and ghosts fly out of the crypt, which is actually a Devil's Gate, an entrance to Hell), and enter the world.

Bobby, Ellen and Sam run to shut the doors of the Devil's Gate. The Yellow-Eyed Demon steps into the cemetery, snatches the Colt from Dean and flings him against a headstone. He thanks Dean for bringing Sam back into the game and prepares to kill him. Suddenly, John appears and wrestles the Demon out of his physical body, giving Dean enough time to grab the Colt and shoot the Demon when he re-enters the body, and kill him.

John then appears to move on and disappears. Sam finds out the truth about his death and what Dean did to save him. In an emotional moment of brotherly love, Sam swears that he will get Dean out of his deal. Even though the Yellow-Eyed Demon died, an army of demons was unleashed; the war has just begun.