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Dean becomes suspicious of Samuel's motives, but Sam isn't sold on the idea that their grandfather is doing anything wrong. The brothers go along on a hunt with Samuel and the other Campbells, but things go terribly awry.
Sam and Dean investigate a series of suicides and discover the victims were being told brutal truths that drove them crazy. They find out someone is invoking the Goddess of Truth, Veritas, forcing people to be cruelly honest against their will and Dean is the next victim. Dean is forced to tell Sam the truth about how he feels about his return from Hell.
Dean and Sam investigate what seems to be a werewolf killing but turns out to be a skinwalker posing as a family dog who is taking revenge on his owner's enemies. After capturing the dog, he turns human and tells Sam and Dean that an Alpha skinwalker has created many sleeper cells that will rise on his command and kill their families.
The sixth season begins about a year after the end happenings of the fifth with Dean living a normal life with Lisa Braeden and her son Ben. Sam mysteriously and miraculously returns to Earth and reunites with Dean, who leaves his new life behind. Sam has been working with their grandfather, Samuel Campbell (their mother's father), in order to capture the Alpha monsters (first of the gene pool). Bobby eventually gets his soul back from the crossroads demon Crowley, who has apparently become the King of Hell. It is eventually discovered that Samuel is following Crowley's orders in exchange for the resurrection of his daughter, Sam and Dean's mother. Castiel is barely helpful anymore because a civil war in Heaven against the archangel Raphael (who wants to take over Heaven, free both Michael and Lucifer from the Cage, and start the Apocalypse again) has taken its toll. Crowley wants to use the Alpha Monsters to locate Purgatory, a supernatural realm that is filled with the souls of every monster that has ever been killed (vampires, werewolves, wendigos, skinwalkers, even shapeshifters etc.) and in which there are a vast collection of souls that could be used for power. Castiel brought back Sam without his soul, and Dean implores the help of the Horseman Death in order to retrieve it. Death puts a wall up in Sam's mind so that he will not remember Hell. Sam's original personality is restored with no memory of the past year and a half. It turns out Castiel made a deal with Crowley for both of them to receive half of the souls in Purgatory. Dean doesn't like the idea and tries to stop the duo. To stop the Winchesters and Bobby Singer, Castiel knocks down the mental barrier in Sam. Castiel betrays Crowley, who then allies himself with Raphael and performs the ritual to open the doors of Purgatory. It fails because they had fake dog's blood and Castiel appears full of power from having done the ritual himself. He obliterates Raphael and Crowley escapes. When the Winchesters try to reason with Castiel, he reveals that he is not an angel anymore, he has become the new God.