Abstract The recognition and cleavage of gasdermin family members by proteases trigger the activation of the pore-forming activities of gasdermins. A prominent example is the targeting of gasdermin D (GSDMD) by inflammatory caspases-1/4/5/11 as an essential step in initiating pyroptosis following inflammasome activation. Previous work has identified cleavage site signatures in substrates such as GSDMD and inflammatory cytokines, but it is unclear if these are the sole determinants for caspase engagement. Here we describe structural studies of a complex between caspase-1 (CASP1) and the full-length GSDMD, which reveals that the cleavage site-containing linker in GSDMD adopts a long loop structure that engages the CASP1 active site. In addition, an exosite is observed between the caspase-1 L2 and L2′ loops and a hydrophobic pocket within the GSDMD C-terminal domain distal to its N-terminal domain. The exosites endows a novel function for the GSDMD C-terminal domain as a caspase-recruitment module, in addition to its role in autoinhibition. The dual site recognition may allow stringent substrate selectivity while facilitating cleavage and pyroptosis upon inflammasome activation. The residues forming the hydrophobic pocket are conserved between human and murine GSDMD, but not in GSDME, suggesting that the exosite interface may underlie the specific recognition of GSDMD but not GSDME by inflammatory caspases. Such mode of dual site recognition may be applicable to other physiological substrates of caspases.