In the aftermath of the car crash, the surviving Winchesters go to the hospital, where one is stalked by a Reaper while another must consider sacrificing himself to save the others.
After the events at the hospital, the brothers have no idea where the demon that killed their mother is hiding. While biding their time trying to come up with an idea, they investigate murders committed by a killer clown.
Dean and Sam investigate the death of a young college student who died in a car accident, but whose grave is now surrounded by a circle of dead plants.
Sam and Dean meet Andy Gallagher, a slacker with psychic powers of persuasion. Once the brothers learn that Andy's family was visited by the Demon, Sam wonders if he could be one of the special children.
Sam and Dean meet up with America's first serial killer, while Jo lies to her mother about going to Vegas and joins Sam and Dean to help them on their hunt.
Sam has a vision of Dean shooting a defenseless man, and they go to the town of River Grove, where they find the townspeople have been possessed by a virus that makes them violent.
Sam and Dean investigate an Connecticut inn run by a single mother where mysterious deaths are taking place. They find evidence of Hoodoo, and try to figure out who is causing the chaos.
Sam and Dean allow themselves to be arrested in order to investigate a series of murders inside a penitentiary. However things get complicated when FBI agent Henricksen shows up to take over their case.
Dean hits an emotional rock bottom after a devastating personal loss. The Yellow Eyed Demon begins a calculated strategic move to unleash the armies of hell.