The gasdermin (GSDM) family plays a critical role in immunity and disease, particularly in pyroptosis, a form of programmed cell death. GSDMs are pore-forming proteins involved in membrane permeabilization, pyroptosis, and inflammatory responses. They are implicated in various diseases, including sepsis, viral infections, and cancer, either through pyroptosis or independently. Inhibiting GSDMD, a key member of the family, is a promising therapeutic strategy. Current inhibitors target GSDMD by binding, blocking cleavage, or inhibiting oligomerization, though some off-target effects occur. This review explores the interplay between GSDMs and pyroptosis, their activation mechanisms, disease associations, and recent advancements in GSDMD inhibitor development. GSDMs are a gene family with conserved structural motifs. Initial studies in the early 2000s identified GSDM as a gene associated with deafness. Subsequent research expanded the GSDM family, revealing roles in various diseases. GSDMD, initially recognized as a mediator of inflammasome-triggered pyroptosis, is highly involved in multiple disease-associated inflammasions. Activation of GSDMD leads to cleavage, releasing N-terminal (NT) fragments that form pores in the plasma membrane, triggering inflammatory cell death and cytokine release. GSDMs are emerging as attractive targets for immune response, inflammation, cancer, and autoimmune disorders. Recent studies have identified small molecule inhibitors targeting GSDMD, showing promise in preclinical models. These inhibitors have progressed from preclinical studies to human trials, highlighting their potential in treating inflammatory conditions. Understanding GSDMD inhibitors' roles in specific diseases is crucial for clinical applications. Research has revealed that GSDMs, including GSDMD, play roles in various cellular processes beyond pyroptosis, such as autophagy, necroptosis, and apoptosis. GSDMD is involved in mitochondrial oxidative stress and mitophagy. The NT domains of GSDMD initiate the release of mitochondrial reactive oxygen species (mtROS), triggering pyroptosis through the NLRP3/GSDMD axis or necroptosis via the MLKL pathway. GSDMD also facilitates the release of cytochrome c, activating caspase-3-mediated apoptosis. Pyroptosis is a newly discovered programmed cell death dependent on GSDM pores, often following activation of inflammatory caspases. It involves membrane rupture, release of intracellular contents, and robust inflammatory responses. The canonical pyroptosis pathway is triggered by inflammasome assembly, activating caspase-1, which cleaves GSDMD and matures pro-IL-1β and pro-IL-18. The non-canonical pathway involves caspase-11/4/5 activation, leading to GSDMD cleavage and pore formation. GThe gasdermin (GSDM) family plays a critical role in immunity and disease, particularly in pyroptosis, a form of programmed cell death. GSDMs are pore-forming proteins involved in membrane permeabilization, pyroptosis, and inflammatory responses. They are implicated in various diseases, including sepsis, viral infections, and cancer, either through pyroptosis or independently. Inhibiting GSDMD, a key member of the family, is a promising therapeutic strategy. Current inhibitors target GSDMD by binding, blocking cleavage, or inhibiting oligomerization, though some off-target effects occur. This review explores the interplay between GSDMs and pyroptosis, their activation mechanisms, disease associations, and recent advancements in GSDMD inhibitor development. GSDMs are a gene family with conserved structural motifs. Initial studies in the early 2000s identified GSDM as a gene associated with deafness. Subsequent research expanded the GSDM family, revealing roles in various diseases. GSDMD, initially recognized as a mediator of inflammasome-triggered pyroptosis, is highly involved in multiple disease-associated inflammasions. Activation of GSDMD leads to cleavage, releasing N-terminal (NT) fragments that form pores in the plasma membrane, triggering inflammatory cell death and cytokine release. GSDMs are emerging as attractive targets for immune response, inflammation, cancer, and autoimmune disorders. Recent studies have identified small molecule inhibitors targeting GSDMD, showing promise in preclinical models. These inhibitors have progressed from preclinical studies to human trials, highlighting their potential in treating inflammatory conditions. Understanding GSDMD inhibitors' roles in specific diseases is crucial for clinical applications. Research has revealed that GSDMs, including GSDMD, play roles in various cellular processes beyond pyroptosis, such as autophagy, necroptosis, and apoptosis. GSDMD is involved in mitochondrial oxidative stress and mitophagy. The NT domains of GSDMD initiate the release of mitochondrial reactive oxygen species (mtROS), triggering pyroptosis through the NLRP3/GSDMD axis or necroptosis via the MLKL pathway. GSDMD also facilitates the release of cytochrome c, activating caspase-3-mediated apoptosis. Pyroptosis is a newly discovered programmed cell death dependent on GSDM pores, often following activation of inflammatory caspases. It involves membrane rupture, release of intracellular contents, and robust inflammatory responses. The canonical pyroptosis pathway is triggered by inflammasome assembly, activating caspase-1, which cleaves GSDMD and matures pro-IL-1β and pro-IL-18. The non-canonical pathway involves caspase-11/4/5 activation, leading to GSDMD cleavage and pore formation. G