We present experimental laboratory evidence and field observations of an autocatalyzed, programmed cell death (PCD) pathway in the nitrogen-fixing cyanobacterium Trichodesmium spp., which forms massive blooms in the subtropical and tropical oceans. The PCD pathway was induced in response to phosphorus and iron starvation as well as high irradiance and oxidative stress. Transmission electron microscopy revealed morphological degradation of internal components including thylakoids, carboxysomes, and gas vesicles, whereas the plasma membranes remained intact. Physiologically stressed cells displayed significantly elevated endonuclease activity and terminal d-UTP nick-end labeling. Nucleic acid degradation was concordant with increased immunoreactivity to human caspase-3 polyclonal antisera and enhanced cleavage of a caspase-specific substrate, DEVD. Caspase activity was positively correlated with mortality and was inhibited by the irreversible caspase inhibitor Z-VAD-FMK. A search of the Trichodesmium erythraeum genome identified several protein sequences containing a conserved caspase domain structure, including the histidine- and cysteine-containing catalytic diad found in true caspases, paracaspases, and metacaspases. Induction of PCD by caspase-like proteases in a bacterial photoautotroph with an ancient evolutionary history requires a reassessment about the origins and roles of cell death cascades. This process is a previously unappriciated mortality mechanism that can lead to the termination of natural Trichodesmium blooms and that can influence the fluxes of organic matter in the ocean.