Set in Baltimore, Maryland, the plot revolves around Macon Leary, a writer of travel guides whose son has been killed in a shooting at a fast-food restaurant. He and his wife Sarah, separately lost in grief, find their marriage disintegrating until she eventually moves out. When he becomes incapacitated due to a fall involving his disturbed dog and one of his crazy home inventions, he returns to the family home to stay with his eccentric siblings—sister Rose and brothers Porter and Charles. The siblings' odd habits include alphabetizing the groceries in the kitchen cabinets and ignoring the ringing telephone. When his publisher, Julian, comes to visit, Julian finds himself attracted to Rose. They eventually marry, though Rose later somehow leaves him to move back in with her brothers.
Macon hires Muriel Pritchett, a quirky young woman with a sickly son, to train his unruly dog, and soon finds himself drifting into a relationship with the two of them. Muriel is the exact opposite of Macon's wife: brash, talkative, pushy, less "classy" and less educated, and fond of wearing eccentric outfits. Despite his initial resistance to this relationship, Macon finds that he is constantly surprised by Muriel's perceptiveness, strength and optimism, as well as her quirky habits and ability to listen. Macon's natural love of the familiar and resistance to commitment results in a relationship that is quite a struggle between the pushy Muriel and the passive Macon. But over time, Macon becomes attached to both Muriel and Alexander, the son, and moves in with them in their tawdry little house. Macon slowly finds that he loves "the surprise of her, and also the surprise of himself when he was with her. In the foreign country that was Singleton Street he was an entirely different person." When his wife Sarah becomes aware of the situation, she decides they should reconcile, forcing him to make a difficult decision about his future.