Lost in Yonkers is a coming-of-age story set in Yonkers, New York.  Simon's Tony and Pulitzer Prize-winning play centres around two brothers, Arty and Jay, who live with their grandmother and their mentally challenged Aunt Bella, while their father travels, desperately trying to scrape enough money together while working as a salesman to pay off his debts to a loan shark, and their mother has died of cancer.

Over the course of the play, the young boys learn lessons about love, responsibility and the importance of family that will carry them into adulthood.