Acute occlusion of a coronary artery can result in myocardial infarction-a leading cause of premature death. Prompt restoration of blood flow to the myocardium can prevent excessive death of cardiomyocytes and improve clinical outcome. Although the major mechanism of cell death after reperfusion is necrosis, it is now recognized that many other cell death pathways may be involved in ischemia-reperfusion (I/R) injury. Pyroptosis is one such cell death pathway that is caspase-1-dependent and induced in response to cellular insult. The activated caspase-1 protease cleaves and activates specific cellular targets including gasdermin D and the proinflammatory cytokines interleukin-1β and interleukin-18. The N-terminal fragment of gasdermin D forms plasma membrane pores resulting in cytosolic leakage and cell rupture, releasing interleukin-1β and interleukin-18. Evidence suggests that inflammation induced by I/R through the pyroptotic pathway contributes to cardiomyocyte death, excessive scar formation, and poor ventricular remodeling. For this reason, there is growing interest in targeting components of the pyroptotic pathway as a means of reducing I/R injury.