Harry (Crystal) and Sally (Ryan) first meet when she gives him a ride to New York after they both graduate from the University of Chicago. As the film journeys through their lives, we see their search for love is not all that successful as they bump into one another, time and time again. Friendship blooms between them, and they enjoy having a friend of the opposite sex. But they are soon confronted with the problem: "Can a man and a woman be friends without sex getting in the way?"