A.J. Manglehorn is a reclusive Texas key-maker who spends his days caring for his cat, finding comfort in his work and lamenting a long lost love. Enter kind-hearted bank teller Dawn whose interest in the eccentric Manglehorn may just be able to draw him out of his shell.

Misanthropic Dr. John Becker runs a clinic in New York City. He is assisted by super-capable Margaret Wyborn and less-than-capable Linda, who's only kept on because no one else can stand the doctor. Becker's best (some would say only) friend is the blind Jake Malinak, who runs a newsstand in the diner across the street. The diner used to be run by Reggie Kostas, but it has been taken over by Chris Conner, a lady whom Becker fluctuates between loathing and being attracted to. The diner is also frequented by Robert Benito, who is universally known as Bob and is the super at Becker's apartment (much to the doctor's regret).