Manhattanites Eleanor (Geena Davis) and Fredrick Little (Hugh Laurie) go to an orphanage to adopt a little brother for their son George (Jonathan Lipnicki). Despite warnings not to adopt across species lines, they end up taking home Stuart (Michael J, Fox), a cute and talkative white mouse with a terrific wardrobe and a case of incurable optimism. George is understandably not too thrilled that his new little brother is actually little, but warms to him after Stuart helps him win a model boat race in Central Park. The family cat, Snowbell (Nathan Lane), is not so easily swayed and decides to rid the family and the world of Stuart for good. With the aid of his friend Monty (Steve Zahn) and various catnip-addicted alley cats, Snowbell hires two mice, Mr. Reginald 'Reggie' (Bruno Kirby) and Mrs. Camille Stout (Jennifer Tilly) to impersonate Stuart’s long lost parents. They come and take him away from the loving arms of his new family and then abandon him to the cold world of Central Park after dark. Stuart faces trials and tribulations aplenty before finally making his way back home.