Pathogen recognition by the plant immune system leads to defense responses that are often accompanied by a form of regulated cell death known as the hypersensitive response (HR). HR shares some features with regulated necrosis observed in animals. Genetically, HR can be uncoupled from local defense responses at the site of infection and its role in immunity may be to activate systemic responses in distal parts of the organism. Recent advances in the field reveal conserved cell death-specific signaling modules that are assembled by immune receptors in response to pathogen-derived effectors. The structural elucidation of the plant resistosome-an inflammasome-like structure that may attach to the plasma membrane on activation-opens the possibility that HR cell death is mediated by the formation of pores at the plasma membrane. Necrotrophic pathogens that feed on dead tissue have evolved strategies to trigger the HR cell death pathway as a survival strategy. Ectopic activation of immunomodulators during autoimmune reactions can also promote HR cell death. In this perspective, we discuss the role and regulation of HR in these different contexts.