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Sam continues his efforts to save Dean from the Mark of Cain. Crowley realizes Dean's demonic antics are starting to cause problems for him in Hell so he searches out an unlikely ally - Castiel.
Crowley notices Dean is becoming more and more aggressive. Dean tells him that's the side effect of being a demon, but Crowley knows it's something more - the Mark of Cain needs to be fed. Meanwhile, Sam is captured by Cole, an angry man who blames Dean for his father's death years ago and wants revenge. Cole tortures Sam, hoping he'll tell him where Dean is hiding. Hannah sees how weak Castiel is becoming as his grace continues to fade, so she makes a bold choice and asks Metatron for help.
A recent string of werewolf attacks points to a surprising culprit - Kate, the werewolf Sam and Dean let live.
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.