Stacy (Krysten Ritter) and Goody (Alicia Silverstone), are two vampires enjoying life in New York City. Goody was turned in 1841 by the vampire Ciccerus (Sigourney Weaver). After leaving the man she fell in love with in the 1960s, she struggled with her life as a vampire until Stacy was turned by Ciccerus sometime during the early 1990s. Goody was able to teach Stacy how to use her new abilities, like sustaining themselves on rat blood, while Stacy helps Goody stay youthful and trendy. Goody keeps her actual age a secret because she is afraid of being viewed as old by Stacy. While at a vampire meeting, Goody discovers that if their maker or "stem" Ciccerus is ever killed, she and Stacy would revert to their human ages.
While working at a hospital as an exterminator, Goody runs into her ex-boyfriend Danny (Richard Lewis), whom she has not seen since the 1960s. They re-connect under the pretense that she is Goody's daughter, but Danny eventually learns the truth when he sees her bite into another man to prevent a stroke. When he asks why she left him, Goody explains that even though she loved him, she did not want to stand in his way of finding someone he could actually build a life with.
Meanwhile, the government is using the Patriot Act to track down vampires, causing panic amongst the vampire's anonymous group. Goody comes up with a plan to delete and change all the information about all the vampires in the New York area during a solar eclipse. After they succeed the vamps throw a party for both human and non-human feeders, but all is endangered by the threat of Ciccerus who didn't attend and massacred an entire restaurant full of people.
Stacy begins a relationship with a young college student named Joey (Dan Stevens). It is soon revealed that Joey is the son of the infamous vampire slayer Dr. Van Helsing (Wallace Shawn) who is in town to find and kill vampires. After spending the night at Joey's place, he sees Stacy crawling down the side of his apartment building in order to get home before the sun rises. Despite his initial shock, Joey accepts that Stacy is a vampire and the two resume dating. Stacy soon discovers she is pregnant, and is informed that the baby won't survive unless she becomes human again, which can only happen if they kill Ciccerus.
The girls team up with Joey and Dr. Van Helsing and after a struggle, they end up killing Ciccerus so that Stacy can keep her baby and have a future with Joey. Stacy looks relatively the same despite being forty years old, but Goody rapidly ages into an old woman. Revealing her actual age, Goody accompanies Joey and Stacy to Times Square where Goody reminisces about her life. As the sun rises, she disintegrates into ash.
A few years later, Stacy and Joey show up at Dr. Van Helsing's house to pick up their young daughter, whom they have named after Goody. As Van Helsing plays with his granddaughter, he notices that the little girl sports a set of vampire fangs, but rather than being horrified he seems amused.
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