Sookie Stackhouse, a waitress with telepathic abilities, falls under the spell of a 173-year-old vampire; Sookie's brother finds himself in hot water.

In a society where humans and vampires co-exist, set in the small town of Bon Temps, Louisiana, Sookie Stackhouse is a young woman who may have found a perfect boyfriend. Sookie is clairvoyant and constantly hears people's thoughts so it makes dating a bit difficult since she tries to keep her ability a secret. When 173-year-old vampire Bill Compton walks into the Merlotte's Bar and Grill where she works as a waitress, she realizes that she can't "hear" what he's thinking, thus giving away his origins since she can't hear the thoughts of those whom are technically dead. Vampires "came out of the coffin" two years ago when the Japanese invented Tru Blood, a synthetic blood substitute. Sookie rescues Bill when a couple of lowlife rednecks, the Rattrays, try to steal his blood to sell on the black market, but she may have a price to pay for interfering. Meanwhile, Sookie's older brother, Jason, is a smooth-talking hustler and lothario who works part-time with a construction crew, and who gets arrested after a local woman that he had a one-night stand with is found strangled. Tara Thornton is Sookie's ill-tempered best friend whom finds her bad-boy brother irresistible. Sam Merlotte is the owner of Merlotte's Bar, who keeps his romantic feelings for Sookie to himself. Lafayette Reynolds is Tara's flamboyant gay cousin and the short-order cook at Merlotte's as well as Jason's co-worker at his construction day job who has more to offer than his gourmet foods. Arlene Fowler is a middle-aged divorcée and another of Sookie's friends and co-workers at Merlotte's looking for a new husband to help raise her two children. Andy Bellefleur is the local police detective working with the collaboration of the town sheriff, Bud Dearborn, who thinks the town may have a killer in their midst as they investigate the strangulation case.

In the aftermath of Roman's death, Russell and the other followers of Lilith celebrate their victory. Bill and Eric don't quite know what it all means for them but a taste of Lilith's blood sends them on a rampaging lust for blood. Eric gets advice from someone from his past. Sookie learns from her new friends in the faerie bar that her powers may be finite. Hoyt's new friends are the vampire-haters who shot Sam and Luna. Hoyt decides to join them and they set their sights on their next target: Jessica. Alcide prepares to fight for the leadership of the pack. Lafayette travels to Mexico to face his nemesis.

The Authority begins to carry out its plan to destroy the five True Blood factories in the world, as per Bill's suggestion. Eric can't quite believe Bill's take on the situation and plans to leave, taking his sister with him. Jessica tells Andy Bellefleur and Sam Merlotte about her kidnapping and what may have happened to Hoyt. They get a lead on the group's leader and get there just in time. Alcide, now an outcast from his pack, visits his father. Russell Edgington visits the pack and takes one of them. With Lafayette's help, Sookie gets a lead on who killed her parents. She also gets a visit from her faerie friends who warn her that vampires are out to take over the world.