Pyroptosis was long regarded as caspase-1-mediated monocyte death in response to certain bacterial insults. Caspase-1 is activated upon various infectious and immunological challenges through different inflammasomes. The discovery of caspase-11/4/5 function in sensing intracellular lipopolysaccharide expands the spectrum of pyroptosis mediators and also reveals that pyroptosis is not cell type specific. Recent studies identified the pyroptosis executioner, gasdermin D (GSDMD), a substrate of both caspase-1 and caspase-11/4/5. GSDMD represents a large gasdermin family bearing a novel membrane pore-forming activity. Thus, pyroptosis is redefined as gasdermin-mediated programmed necrosis. Gasdermins are associated with various genetic diseases, but their cellular function and mechanism of activation (except for GSDMD) are unknown. The gasdermin family suggests a new area of research on pyroptosis function in immunity, disease, and beyond. The necrotic nature of pyroptosis was not well appreciated for decades and it was misregarded as a special type of apoptosis in monocytes due to the involvement of a caspase (caspase-1). Characterization of inflammasomes establishes caspase-1-mediated pyroptosis as a general innate immune effector mechanism. Caspase-4, 5, and 11, expressed also in nonmonocytic cells, induce pyroptosis upon recognition of intracellular lipopolysaccharide. The role of caspase-11 in endotoxic shock emphasizes the physiological importance of pyroptosis. Both caspase-1 and caspase-11/4/5 cleave gasdermin D (GSDMD), a gasdermin-family member, to release its gasdermin-N domain that perforates the plasma membrane to induce cell swelling and osmotic lysis. Nearly all gasdermins share the pore-forming and pyroptotic activity of GSDMD. Several gasdermins are associated with genetic diseases but their function and activation mechanism are unknown.