At 3 o'clock one morning, Captain Denis Cathcart, the fiancé of Wimsey's sister Lady Mary, is found shot dead just outside the conservatory.

Wimsey arrives to investigate, along with his friend Inspector Charles Parker, who will find himself becoming increasingly attracted to Lady Mary throughout the novel.

Mary assumed that he was the killer and has been covering for him, but when she learns that he had fled in terror after discovering the body, she breaks off their engagement in disgust at his cowardice.

Wimsey travels to New York to find her, makes a daring and dangerous transatlantic flight back to London, and arrives just in time to present his evidence at Denver's trial in the House of Lords.

In the final scene of the book, Inspector Sugg finds Wimsey, Parker, and a friend on the street after midnight, hopelessly drunk, celebrating the end of the case.

The book's title derives from the Epistle to the Hebrews, chapter 12, verse 1:[2] "Wherefore seeing we also are compassed about with so great a cloud of witnesses, let us lay aside every weight, and the sin which doth so easily beset us, and let us run with patience the race that is set before us.

"[4] In his 2017 overview of the classic crime genre, Martin Edwards suggests that Clouds of Witness is the work of a novelist learning her craft, but that it displays the storytelling qualities that soon made Sayers famous.

In this wintry weather he is braving a peril which would appal any heart but his own and that of the world-famous aviator whose help he has enlisted, so that no moment may be lost in freeing his noble brother from this terrible charge.