Here we report that S-palmitoylation at Cys191 of GSDMD enables pore formation by both cleaved GSDMD N-terminal domain (GSDMD-NT) and intact GSDMD. Inflammasome activation-induced GSDMD palmitoylation is dependent on a feed-forward loop, as palmitoylated GSDMD (both intact and NT) damages mitochondria, leading to more ROS, which in turn enhances palmitoylation. The cleavage-deficient D275A mutant of GSDMD reconstituted into GSDMD knockout macrophages is palmitoylated after inflammasome stimulation and significantly elicits cell death and IL-1? release. Palmitoylated intact WT or uncleavable D275A GSDMD induced liposome leakage and formed pores similar in morphology to GSDMD-NT pores shown by electron microscopy (EM). These data challenge the concept that cleavage is the only trigger for GSDMD activation and uncover the surprising new paradigm that ROS-promoted palmitoylation is required for pore formation by both GSDMD-NT and intact GSDMD and may serve as a general switch for the activation of this pore-forming family.