Gasdermins are membrane pore-forming proteins that cause pyroptosis, an inflammatory cell death in which cells burst and release cytokines, chemokines, and other host alarm signals, such as ATP and HMGB1, which recruit and activate immune cells at sites of infection and danger. There are five gasdermins in humans - gasdermins A to E. Pyroptosis was first described in myeloid cells and mucosal epithelia, which express gasdermin D and activate it when cytosolic sensors of invasive infection or tissue damage assemble into large macromolecular structures, called inflammasomes. Inflammasomes recruit and activate inflammatory caspases (caspase 1, 4, 5, and 11), which cut gasdermin D to remove an inhibitory C-terminal domain, allowing the N-terminal domain to bind to membrane acidic lipids and oligomerize into pores. Recent studies have identified inflammasome-independent proteolytic pathways that activate gasdermin D and the other gasdermins. Here, we review inflammasome-independent pyroptosis pathways and what is known about their role in normal physiology and disease.