The musical revolves around the antics of Mame Dennis, a fun-loving, wealthy eccentric with a flare for life and a razor sharp wit. Her life is suddenly changed when she becomes the guardian of her late brother's only child, Patrick Dennis. Her adventures take us from the speak-easies of the roaring 20's to the depression following the great Stock Market crash. She is rescued by a wealthy Southern plantation owner, marries and is widowed suddenly, and through it all, manages to keep things under control. With some help from her dearest friend, Vera Charles, she helps keep things at 3 Beekman Place a rousing free-for-all.

While traveling through the desert for an appointment with a client, the businessman David Mann from California passes a slow and old tanker truck. The psychotic truck driver feels offended and chases David along the empty highway trying to kill him.