Autoinflammatory diseases are characterized by unprovoked inflammation without high-titer autoantibodies or antigen-specific T cells. These diseases, first identified in hereditary periodic fever syndromes, have gained recognition due to advances in understanding their genetic basis and the role of the innate immune system. This review proposes an updated classification based on molecular insights, replacing a clinical classification that is less informative. The six categories include IL-1β activation disorders (inflammasomopathies), NF-κB activation syndromes, protein misfolding disorders, complement regulatory diseases, cytokine signaling disturbances, and macrophage activation syndromes. The classification reflects both clinical and molecular aspects, suggesting new hypotheses and therapeutic targets. IL-1β activation disorders, such as cryopyrinopathies, are caused by mutations in NLRP3, leading to dysregulated inflammasome activity. These mutations can be intrinsic or extrinsic, affecting either the inflammasome components or upstream/downstream regulatory elements. NLRP3 is a key component of the inflammasome, which activates caspase-1 and processes IL-1β. Mutations in NLRP3 can lead to constitutive IL-1β production, bypassing the need for ATP. Other autoinflammatory diseases, such as familial Mediterranean fever (FMF), are caused by mutations in MEFV, which affect pyrin function. Pyrin interacts with ASC and NLRP3, influencing inflammasome activity and IL-1β production. FMF is classified as an extrinsic inflammasomopathy, with mutations in pyrin leading to proinflammatory effects. PAPA syndrome is caused by mutations in PSTPIP1, which interact with pyrin and affect inflammasome activity. These mutations may also influence T cell activation, contributing to autoinflammatory symptoms. CRMO and SAPHO syndromes are classified as disorders of IL-1β inflammasome regulation, with mutations in Pstpip2 affecting innate immune responses. HIDS is caused by mutations in MVK, leading to mevalonate kinase deficiency and altered isoprenoid biosynthesis, which may affect signaling pathways and IL-1β production. These diseases highlight the importance of the innate immune system in autoinflammatory conditions and suggest new therapeutic targets, such as IL-1β inhibitors. The classification of autoinflammatory diseases based on molecular pathophysiology provides a framework for understanding their mechanisms and developing targeted therapies.Autoinflammatory diseases are characterized by unprovoked inflammation without high-titer autoantibodies or antigen-specific T cells. These diseases, first identified in hereditary periodic fever syndromes, have gained recognition due to advances in understanding their genetic basis and the role of the innate immune system. This review proposes an updated classification based on molecular insights, replacing a clinical classification that is less informative. The six categories include IL-1β activation disorders (inflammasomopathies), NF-κB activation syndromes, protein misfolding disorders, complement regulatory diseases, cytokine signaling disturbances, and macrophage activation syndromes. The classification reflects both clinical and molecular aspects, suggesting new hypotheses and therapeutic targets. IL-1β activation disorders, such as cryopyrinopathies, are caused by mutations in NLRP3, leading to dysregulated inflammasome activity. These mutations can be intrinsic or extrinsic, affecting either the inflammasome components or upstream/downstream regulatory elements. NLRP3 is a key component of the inflammasome, which activates caspase-1 and processes IL-1β. Mutations in NLRP3 can lead to constitutive IL-1β production, bypassing the need for ATP. Other autoinflammatory diseases, such as familial Mediterranean fever (FMF), are caused by mutations in MEFV, which affect pyrin function. Pyrin interacts with ASC and NLRP3, influencing inflammasome activity and IL-1β production. FMF is classified as an extrinsic inflammasomopathy, with mutations in pyrin leading to proinflammatory effects. PAPA syndrome is caused by mutations in PSTPIP1, which interact with pyrin and affect inflammasome activity. These mutations may also influence T cell activation, contributing to autoinflammatory symptoms. CRMO and SAPHO syndromes are classified as disorders of IL-1β inflammasome regulation, with mutations in Pstpip2 affecting innate immune responses. HIDS is caused by mutations in MVK, leading to mevalonate kinase deficiency and altered isoprenoid biosynthesis, which may affect signaling pathways and IL-1β production. These diseases highlight the importance of the innate immune system in autoinflammatory conditions and suggest new therapeutic targets, such as IL-1β inhibitors. The classification of autoinflammatory diseases based on molecular pathophysiology provides a framework for understanding their mechanisms and developing targeted therapies.