Vardalos and Collette play Connie and Carla, two struggling Chicago dinner theater performers who accidentally witness a mafia hit who subsequently hit the road, running for their lives. Assuming the killers will never look for them in a place devoid of culture, the pair head to Los Angeles, where they assume new identities and find their middling talent at song and dance perfectly suited to new careers-as drag queens. Much to their surprise, they inadvertently become the toast of the cabaret circuit.

As their ruse becomes increasingly difficult to maintain, they discover that it is indeed lonely at the top, especially after Connie meets Jeff (Duchovny), a guy she'd really like to be a real girl with. With the mafia zeroing in and the line separating their onstage/offstage personas blurring beyond the point of recognition, Connie and Carla soon discover the power of not compromising to pursue your dreams, fighting the good fight, and never, never underestimating the transformative power of cosmetics.