Second only to Slaughterhouse-Five of Vonnegut's canon in its prominence and influence, God Bless You, Mr. Rosewater (1965) presents Eliot Rosewater, an itinerant, semi-crazed millionaire wandering the country in search of heritage and philanthropic outcome, introducing the science fiction writer Kilgore Trout to the world and Vonnegut to the collegiate audience which would soon make him a cult writer.

Trout, modeled according to Vonnegut on the science fiction writer Theodore Sturgeon (with whom Vonnegut had an occasional relationship) is a desperate, impoverished but visionary hack writer who functions for Eliot Rosewater as both conscience and horrid example. Rosewater, seeking to put his inheritance to some meaningful use (his father was an entrepreneur), tries to do good within the context of almost illimitable cynicism and corruption.

It is in this novel that Rosewater wanders into a science fiction conference – an actual annual event in Milford, Pennsylvania – and at the motel delivers his famous monologue evoked by science fiction writers and critics for almost half a century: "None of you can write for sour apples... but you're the only people trying to come to terms with the really terrific things which are happening today." Money does not drive Mr. Rosewater (or the corrupt lawyer who tries to shape the Rosewater fortune) so much as outrage at the human condition.

The novel was adapted for a 1979 Alan Menken musical. The novel is told mostly thru a collection of short stories dealing with Eliot's interactions with the citizens of Rosewater County, usually with the last sentence serving as a punch line. The antagonist's tale, Mushari's, is told in a similar short essay fashion. The stories reveal different hypocrisies of humankind in a darkly humorous fashion.