In August of 2001, Joslin Smith-Simpson is a 12-year-old girl who attends East Side Middle School and lives with her big family in New York City. However, the Smith-Simpson family felt that their apartment in the Bronx was too small for their guests to live in, so they decided to move to a hotel to start a B&B business. One day, Joslin's family announced that they were expanding the hotel for a new bedroom for a new resident; a 17-year-old white blood cell named Osmosis Jones, who is on the verge of turning 18. Along the way, the two meet 6 other teenagers, Hector Cruz, Maria Amino, Christine Kolchuck, Leah Estrogen, Paul Spryman, and Drix Koldreliff, and together, the 9 kids get into several antics and chaos.