Guido and Vincent are childhood best friends—third cousins, really—living in Cambridge and dreaming about their futures. Guido plans to write poetry while Vincent feels confident he will win a Nobel prize for physics. When Guido spots Holly while exiting a museum, he can immediately sense that she will difficult, quirky, and hard to live with. He loves her on sight. Vincent, open-minded and cheerful, meets Misty at work. Though she is a bored and misanthropic brunette, he finds himself desperate to know her.

Through courtship, jealousy, estrangement, and other perils, Happy All the Time follows four sane, intelligent, and good-intentioned people who manage to find love in spite of themselves.