The intersegmental muscles of the tobacco hawkmoth Manduca sexta die during the 36-hr period after metamorphosis. The trigger for cell death is a fall in the ecdysteroid titer. Commitment of the intersegmental muscles to degenerate involves selective repression and activation of ecdysteroid-responsive genes. When the pattern of gene expression is altered after injection of either 20-hydroxyecdysone or actinomycin D, the muscles persist. cDNA clones have been isolated for four genes that become abundantly expressed coincident with the commitment to degenerate. The data presented here indicate that programmed cell death is not due to the cessation of macromolecular synthesis in condemned cells but rather is due to the activation of a differentiative pathway.