The gasdermin (GSDM) family, a recently characterized class of pore-forming effector proteins, plays a crucial role in pyroptosis and various diseases. GSDMs are involved in membrane permeabilization, pyroptosis, and inflammatory responses, which are essential for defending against irritants and infections. The regulation of GSDM-mediated pyroptosis is emerging as a promising therapeutic strategy for treating diseases such as sepsis, viral infections, and cancer. Current approaches to inhibit GSDMD primarily involve binding to GSDMD, blocking its cleavage, or inhibiting its N-terminal (NT) oligomerization, though these methods have some off-target effects. This review delves into the interplay between GSDMs and pyroptosis, the activation mechanisms of GSDMs, their associations with diseases, and recent advancements in developing GSDMD inhibitors. GSDMs have been implicated in a wide range of diseases, including sepsis, viral infections, and cancer, either through their involvement in pyroptosis or independently. The review highlights the potential of GSDMD inhibitors in treating specific disease indications and discusses the advantages and disadvantages of inhibiting GSDMD-mediated pyroptosis. The history of GSDM research is traced from the early 2000s, when the first GSDM gene, GSDM, was cloned, to the recent discovery of the pore-forming capacity of GSDMD and other GSDMs. The review also covers the structural and functional aspects of GSDMs, their roles in pyroptosis, and their involvement in various diseases. It emphasizes the importance of understanding the mechanisms of GSDMs in health and disease states to develop effective therapeutic strategies.The gasdermin (GSDM) family, a recently characterized class of pore-forming effector proteins, plays a crucial role in pyroptosis and various diseases. GSDMs are involved in membrane permeabilization, pyroptosis, and inflammatory responses, which are essential for defending against irritants and infections. The regulation of GSDM-mediated pyroptosis is emerging as a promising therapeutic strategy for treating diseases such as sepsis, viral infections, and cancer. Current approaches to inhibit GSDMD primarily involve binding to GSDMD, blocking its cleavage, or inhibiting its N-terminal (NT) oligomerization, though these methods have some off-target effects. This review delves into the interplay between GSDMs and pyroptosis, the activation mechanisms of GSDMs, their associations with diseases, and recent advancements in developing GSDMD inhibitors. GSDMs have been implicated in a wide range of diseases, including sepsis, viral infections, and cancer, either through their involvement in pyroptosis or independently. The review highlights the potential of GSDMD inhibitors in treating specific disease indications and discusses the advantages and disadvantages of inhibiting GSDMD-mediated pyroptosis. The history of GSDM research is traced from the early 2000s, when the first GSDM gene, GSDM, was cloned, to the recent discovery of the pore-forming capacity of GSDMD and other GSDMs. The review also covers the structural and functional aspects of GSDMs, their roles in pyroptosis, and their involvement in various diseases. It emphasizes the importance of understanding the mechanisms of GSDMs in health and disease states to develop effective therapeutic strategies.