Pyroptosis, originally known to be activated by caspase-1/4/5/11, is critical for immune defenses and development of many immunological diseases. While caspase-1 is downstream of the inflammasome complex that senses infections, caspase-11 and its human counterparts caspase-4/5 serve as cytosolic receptors for bacterial lipopolysaccharide (LPS) to activate pyroptosis-mediated immune defenses. These caspases cleave Gasdermin D (GSDMD) to release the autoinhibition on its Gasdermin-N domain that executes pyroptosis via an intrinsic membrane pore-forming activity. Gsdmd-/- mice are susceptible to various bacterial infections but also resistant to LPS-induced septic shock. GSDMD belongs to a large Gasdermin family sharing the autoinhibited pore-forming domain. Another family member GSDME harbors a caspase-3-recognition motif also in the middle linker region and can switch caspase-3-induced apoptosis to pyroptosis. Similarly, caspase-3 cleavage releases the pore-forming domain of GSDME, and the resulting pyroptosis also occurs in cells treated with DNA-damaging chemotherapy drugs. GSDME is silenced in most cancer cells but expressed in normal tissues. GSDME-positive cells from normal human tissues undergo caspase-3-dependent pyroptosis in response to chemotherapy drugs. Knockdown of GSDME expression in these primary cells converts the death from pyroptosis to apoptosis. Importantly, Gsdme-/- mice are protected from chemotherapy drug-induced tissue damage and weight loss. These findings define pyroptosis as Gasdermin-mediated programmed necrotic cell death that shall have important functions in a wide spectrum of biological and pathological processes.