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Dean, Sam and Castiel deal with Cain's return. Crowley and Rowena continue to grow closer but when Crowley bails on plans with his mother to help the Winchesters, Rowena lets him have it.
Ghost starts killing people through various electronic devices. Sam and Dean discover who was killed and why this ghost is seeking revenge on a group of college students but what they can't figure out is how he's doing it. With three dead, the brothers must stop the ghost before he claims his next victim.
Despite Dean's directive to forget about looking for a cure for the Mark of Cain, Sam continues to do research. Dean suspects Sam is hiding something but decides to focus on a new murder case where they run into Cole. The three team up and learn a Khan worm is infecting men and turning them into murderers. Unfortunately, the worm makes it's way into Cole.
Season 10 begins with Sam's frantic search for his missing brother, who is gone without a trace. The road to recovering the wayward Dean takes Sam down dark paths, with consequences that will shake the boys to their core. Along the way, Sam encounters a former US marine named Cole Trenton, who apparently knows Dean and wants revenge for Dean killing his father. Meanwhile, Castiel, with the aid of Hannah, has to pick up the pieces in the aftermath of Metatron's campaign. But with his grace failing and rogue angels still on the loose, Cas faces the ticking clock of his own mortality. After Sam learns that Dean is a demon, because of Crowley and the Mark of Cain, Sam eventually finds him, with help from Crowley, but so does Cole. While Dean and Cole meet and duke it out, Dean overpowers Cole and nearly kills him. But Sam manages to trap Dean with holy water and handcuffs carved with devils-trap symbols.