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In the book, Poirot is a passenger on board a flight from Paris to Croydon. Some time before landing, one of the passengers, Madame Giselle — a moneylender — is found dead. Initially, a reaction to a wasp sting is postulated, but Poirot spies the true cause of death: a poison-tipped dart, apparently fired from a blowpipe. It becomes apparent that the victim has been murdered.

The answer to the murder is found in a collection of the fellow passengers clothes where a matchbox that could have contained a wasp is found and a white dentists coat that could be used to disguise the murderer as a steward is found. As with many other works in the crime fiction genre, Death in the Clouds is an example of a locked room mystery,