The film begins with Gayle (Amy Poehler), Becky (Parker Posey) and Judi (Rachel Dratch) performing in McCormick State College's Senior Talent Show in 1992. The three of them were the 'losers' and geeks in college but were always hopeful about their future. The next scene then jumps to 15 years later. Gayle is now a guide dog trainer for the visually handicapped. She asks her client out on a date but gets rejected after he touches her face. Becky is an office manager for Senator Hartmann (Jane Lynch). Hartmann refuses to take Becky's ideas seriously and only assigns odd jobs to her.Judi and her fiance, William (Seth Meyers), go for relationship counseling (Loretta Devine) and insist that there are no secrets between them. Becky returns home only to find her cat, Honey, dead. The three of them hold their usual 'make your own pizza party' and play their usual 'movie game'. They decide to go on a trip to Tempe, Arizona to the Wimmin's Music Festival.Senator Hartmann announces to her team that she is the potential next vice president (The current VP was caught in a motel with 2 underage girls). In order to ensure success, she has to make sure that she has a good reputation and background. Ashley (Amber Tamblyn), her daughter, just broke up with her boyfriend Doug (Jonathan Sadowski) because she is not putting out enough. Doug starts dating Mason, the leader of the Sevens, who promote promiscuity and binge drinking.In order to win him back and not disappoint her mother, she decides that she will be going to South Padre for her spring break. She wants her to think that she is 'just like her mother was back in the days' - the most popular girl in her sorority and 'always up for a good time'. In order to make sure that Ashley does not act out, Senator Hartmann sends Becky to go to South Padre to keep an eye on her. Becky is instructed not to reveal her true mission to Ashley under any circumstances.Judi returns home and discovers that William is actually gay, and he ends up breaking off with her. Judi meets up with Becky and Gayle and the three of them decide to go to South Padre to relive the college days that they never had. Even though the girls are appalled with the state of the place (They thought they were staying at the 4 seasons hotel, but it turns to be a run-down Mexican place called the four seasons), Gayle and Judi fit into the crowd easily (Charlene (Missi Pyle) is the bartender at the hotel and its her 18th spring break). The room is trashy and there is a single toilet for the entire floor. They spend the next few days getting wasted (with Charlene, who takes them around town) while Becky keeps to the main reason of her being there (she tracks down Ashley at a local pub/disco, where she is trying to impress Doug and win her back). Throughout the trip, Gayle becomes very close to a group of girls called The Sevens who are Ashley's nemesis. Gayle helps Mason fight off a couple of studs (she says guys are just dogs with thumbs) and Mason is impressed.The ladies head to the beach the following day but are way overdressed. Charlene gets Judi to beer dunk. While Mason gets Gayle dressed properly hot for the beach. Mason wants Gayle to coach the Sevens for the talent show competition. Ashley is pulled in to wrestle in Salsa sauce, and Becky jumps in to rescue her (losing her own top on the process). Ashley and Becky befriend each other. At night, Judi wanders into the wrong room and ends up having sex with a stranger in an orgy.Judi and Gayle invite Becky and Ashley to a foam party organized by Charlene. Ashley finds Doug kissing Mason. Becky doesn't attend and resents Judi and Gayle having too much fun. Gayle and Judi eventually persuade Becky into relaxing as Ashley is a nerd and is not doing anything crazy at all. Next night at another party, Ashely dresses like a slut to attract Doug. Mason sees Ashley and gets her drunk. To show up Doug, she enters a wet T-shirt contest. Mason kissing Ashley on stage. Becky gets on stage and tries to protect Ashley. Ashley finds out that Becky was actually sent by her mother and feels betrayed because she thought they were friends. They engage in a cat fight and end up in jail.That night, William goes to find Judi and asks for a second chance. Then Judi bails Becky and Ashley out of jail. The news of Ashely's wet T-shirt contest and her videos are all over the news by now. Judi announces to everyone that she is going to marry William. Gayle declares that she's going to be in the All Girl Talent Show with The Sevens because she is finally going to win (implying that she was never going to win with Judi and Becky). This leads to an argument, and Judi leaves to get married, while Becky (Supported by Ashley and Charlene) and Gayle (with the sevens) prepare separately for the talent contest. Doug wants Becky back, but she shuts him out.At the airport, Judi finally admits to herself that William is gay and tells him she can't marry him. Gayle falls out with Mason (Sophie Monk) (Mason kicks a dog who was dry humping her), the leader of The Sevens, just before they go on stage. Senator Hartmann appears backstage and wants to bring Ashley back home by force. They have a confrontation and Ashley begs her mother to let her compete in the show, and her mother relents. As the group begins to perform, the pianist passes out (drunk) and Judi returns just in time to replace her. They perform, with begrudged success.The film ends with the three of them back home, at their usual 'make your own pizza party' playing their usual 'movie game'. But now they all have "happening" lives. Hartmann becomes VP. Becky gets her environmental career going. Gayle features on top dog trainer magazines. Judi finally marries a famous singer.