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The fictional universe depicted in the series is premised on the notion that vampires (and other supernatural creatures) have been living among us, unbeknownst to the majority of humans until two years before the series premiere, when the creation of synthetic blood ("Tru Blood") by Japanese scientists allowed vampires to come out of the coffin (a term coined as a play on "coming out of the closet") and reveal their existence to the world on the basis that they no longer need to feed on humans to survive. This so-called 'Great Revelation' has split the vampires of the world into two camps: those who wish to integrate into human society (aka 'mainstream') by campaigning for citizenship and equal rights, and those who think that human-vampire co-existence is impossible because it is in conflict with the inherently violent nature of vampires. Throughout the series, other supernatural creatures are also introduced, among them shapeshifters, werewolves, fairies, witches and a maenad.
The series revolves around Sookie Stackhouse (Anna Paquin), a telepathic Human-Fairy hybrid known as a halfling (not to be confused with similarly named, but unrelated creatures found in other fantasy works.) Sookie is a waitress at Merlotte's Bar and Grill, owned by Sam Merlotte (Sam Trammell) in the small Louisiana town of Bon Temps. Sam is a shapeshifter, though this secret is kept hidden from most of the town. Other characters include Bill Compton (Stephen Moyer), a handsome 173-year-old vampire who has returned to Bon Temps to take up residence in his former home following the death of his last remaining relative; Tara Thornton (Rutina Wesley), Sookie's tough-talking but insecure best friend; Sookie's womanizing brother Jason (Ryan Kwanten); thousand-year-old vampire and Sheriff of Area 5, Eric Northman (Alexander Skarsgård); and Lafayette Reynolds (Nelsan Ellis), a short order cook, drug dealer, road crew member and medium.