In terms of story, Boyarsky said that Diablo III will pick up 20 years after the end of the events in the Diablo II expansion, Lord of Destruction. Deckard Cain, the storyteller and quest giver in the previous games, returns in Diablo III and, at the beginning of the game, is convinced that the forces of Hell are intent on invading Sanctuary. Cain is desperate to find a way to stop this invasion and, it seems will work with your character to that end as the game begins. Worse yet, the general population of the various cities of Sanctuary--traumatized by the events of the previous games--have begun to put those evil events behind them; many believe that the demons that previously appeared in their cities were just myth to begin with.
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