Abstract Systemic autoinflammatory diseases (SAIDs) arise from dysregulated innate immune system activity, which leads to systemic inflammation. These disorders, encompassing a diverse array of genetic defects classified as inborn errors of immunity, are significant diagnostic challenges due to their genetic heterogeneity and varied clinical presentations. Although recent advances in genetic sequencing have facilitated pathogenic gene discovery, approximately 40% of SAIDs patients lack molecular diagnoses. SAIDs have distinct clinical phenotypes, and targeted therapeutic approaches are needed. This review aims to underscore the complexity and clinical significance of SAIDs, focusing on prototypical disorders grouped according to their pathophysiology as follows: (i) inflammasomopathies, characterized by excessive activation of inflammasomes, which induces notable IL-1β release; (ii) relopathies, which are monogenic disorders characterized by dysregulation within the NF-κB signaling pathway; (iii) IL-18/IL-36 signaling pathway defect-induced SAIDs, autoinflammatory conditions defined by a dysregulated balance of IL-18/IL-36 cytokine signaling, leading to uncontrolled inflammation and tissue damage, mainly in the skin; (iv) type I interferonopathies, a diverse group of disorders characterized by uncontrolled production of type I interferons (IFNs), notably interferon α, β, and ε; (v) anti-inflammatory signaling pathway impairment-induced SAIDs, a spectrum of conditions characterized by IL-10 and TGFβ anti-inflammatory pathway disruption; and (vi) miscellaneous and polygenic SAIDs. The latter group includes VEXAS syndrome, chronic recurrent multifocal osteomyelitis/chronic nonbacterial osteomyelitis, Schnitzler syndrome, and Still’s disease, among others, illustrating the heterogeneity of SAIDs and the difficulty in creating a comprehensive classification. Therapeutic strategies involving targeted agents, such as JAK inhibitors, IL-1 blockers, and TNF inhibitors, are tailored to the specific disease phenotypes. (SAIDs activity immunity presentations discovery 40 diagnoses phenotypes needed follows i (i inflammasomopathies inflammasomes IL1β ILβ IL 1β β release ii (ii relopathies NFκB NF κB iii (iii IL18/IL36 IL18IL36 ILIL 18/IL 36 18 IL-18/IL-3 defectinduced defect induced damage skin iv (iv interferonopathies IFNs, IFNs , (IFNs) α ε v (v antiinflammatory anti inflammatory impairmentinduced impairment IL10 10 disruption vi (vi syndrome osteomyelitischronic osteomyelitis Stills Still s others classification agents inhibitors IL1 1 IL- blockers 4 IL18 IL36 IL18/IL3 IL18IL3 18IL 3 IL-18/IL- (IFNs IL3 IL18/IL IL18IL IL-18/IL