Axons are programmed to self-destruct under certain conditions that occur during development, stress, or disease states. Gerdts et al. outline a biochemical mechanism that controls such axon degeneration. Expression of versions of SARM1 (sterile alpha and TIR motif–constraining 1) that could be activated or inhibited in cells revealed that activation of SARM1 was necessary and sufficient to cause axon destruction in cultured mouse neurons. SARM1-mediated destruction was associated with depletion of the metabolic cofactor NAD+ from cells.