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Fiona is the CEO of MegaRecords who uses subliminal messages to manipulate teens' spending. She and her assistant Wyatt Frame are pretending to work with the U.S. Government to manufacture faddish pop bands for consumption by the teenage market. After Josie, Melody, and Valerie are flown to New York City where they are renamed "Josie and the Pussycats", much to the girls' discomfort. All goes well and their first single climbs rapidly to the top of the charts, but Valerie grows increasingly frustrated that all media attention is focused on Josie rather than the band as a whole.
Melody, too simple to notice the undue attention Josie receives, uses her uncanny behavioral perception and becomes suspicious of Fiona and Wyatt. Before Valerie and Melody's suspicions can reveal the conspiracy, Fiona orders Wyatt to kill them. He sends them without Josie to a fake television appearance on the MTV show Total Request Live, where a Carson Daly impersonator and the real Carson Daly assault them with baseball bats. The girls survive due to their attackers' incompetence.
Meanwhile, Wyatt prevents Josie from attending a gig by Alan M, Josie's love interest, by telling her it was canceled. Instead, Josie listens to a remix of their latest single. The remix contains a subliminal message track designed to brainwash her into desiring a solo career, and into seeing Valerie and Melody are impediments to that goal. After an argument with her bandmates, Josie realizes that the recording caused the fight. Her suspicions are confirmed when she uses a mixing board to make the subliminal track audible, but she is caught by Fiona. MegaRecords have organized a giant pay-per-view concert, whereby they plan to unleash their biggest subliminal message yet.
Fiona and Wyatt force Josie to perform solo on stage by holding Melody and Valerie hostage. The badly injured members of Du Jour—who survived by a plane accident orchestrated by Wyatt, but landed in the middle of a Metallica concert where they were severely beaten by Metallica fans—appear just in time to stop Wyatt and Fiona from launching the message. In the resulting fight, Josie destroys the machine used to generate the messages.
The new subliminal message is revealed not to promote the band, the label, or a corporate sponsor, but to make Fiona universally popular. Fiona suffers a breakdown and reveals that in high school she had been a social outcast named "Lisping" Lisa Snyder. Wyatt reveals that his real name is "White-Ass" Wally, his British is false, and his appearance is a disguise. Wally had gone to the same high school as Lisa but was a persecuted and unpopular albino. Lisa and Wally immediately fall in love, but not before Wally reveals his potbelly, which he had been holding in for the past fifteen years. The government agents colluding with Lisa arrive, but because the conspiracy is exposed, they arrest Lisa and Wally as scapegoats to cover up the government's involvement in the failed scheme.