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Posey attended the State University of New York at Purchase, where she roomed with actress Sherry Stringfield. Posey's first break was in television, when she won the role of Tess Shelby on the daytime soap opera As the World Turns. (Stringfield, Posey's roommate, was also cast on the daytime drama Guiding Light at about the same time.) Posey's first major role in a feature film was in Dazed and Confused (1993).

Throughout the late 1990s, Posey starred in a large number of independent films and was named Queen of the Indies by Time Magazine, which cited 32 independent films to her credit, including Personal Velocity, Clockwatchers, Party Girl, and The House of Yes, for which she received especially positive reviews for her portrayal of a delusional woman in love with her own brother. She is part of the acting ensemble that appears in director Christopher Guest's films, including his four mock documentaries (Waiting for Guffman in 1996, Best in Show in 2000, A Mighty Wind in 2003, and For Your Consideration in 2006). Posey is also a favorite of director Hal Hartley. She appeared in Henry Fool (1998), two of his shorts, Opera No. 1 (1994) (with Adrienne Shelley, another Hartley regular) and "Sisters of Mercy" (2004). Posey also starred in his most recent film, Fay Grim (2006).  Posey received acclaim for her performance in Zoe Cassavetes directorial debut Broken English in 2007.

Posey has had supporting roles in several big budget studio films, including  Scream 3 (2000), You've Got Mail (1998), Josie and the Pussycats (2001), Laws of Attraction (2004) and Blade: Trinity (2004). She also had a small but notable performance in Superman Returns, playing

Kitty Kowalski, an assistant to villain Lex Luthor.