College "frenemies" Lauren and Katie move in together after losing a relationship and rent control, respectively. Sharing Katie's late grandmother's apartment in New York City, the girls bicker with each other until one fateful night, when Katie's noisy bedroom activities make Lauren barge in and discover a dirty little secret. This revelation brings them closer together, and Lauren (the brains) and Katie (the talent) concoct a wildly successful business venture. As profits swell, the girls reevaluate their hopes and dreams and realize that just because someone pees in your hair in college doesn't mean she won't be your best friend 10 years later.
Restless and unhappy, two couples get caught up in infidelity and deception. Barry is a sullen businessman married to Mary, a writer who is unsatisfied with their relationship. Mary begins an affair with Jerry, a smug theater professor and husband of her friend, Terri, who is also a writer. Adding to the adulterous mix are Cary, a callous doctor, and Cheri, an art-gallery assistant.
In post-9/11 New York City, an eclectic group of citizens find their lives entangled, personally, romantically, and sexually, at Shortbus, an underground Brooklyn salon infamous for its blend of art, music, politics, and carnality.