Axons contain a protein, Sarm1, capable of triggering their self-destruction. It is crucial that such a protein be kept in an ‘off’ state or neurodegeneration will occur. In the current paper from the DiAntonio and Milbrandt labs at Washington University and the Hao Wu lab at Harvard University, Multiple domain interfaces mediate SARM1 autoinhibition, they used cryo-EM, mutational analysis, and peptide mapping to identify domains and interactions responsible for maintaining the ‘off’ state.