Inflammation is a physiologic defense mechanism against an out-side attack. Usually, it resolves after the removal of noxious causes, but systemic autoinflammatory disorders (SAIDs) have recurrent or repeated acute inflammation through uncontrolled gene function, which can present as gain-of-function or loss-of-function of a gene during inflammation. Most SAIDs are hereditary autoinflammatory diseases and develop by dysregulation of innate immunity through various pathways including inflammasomes, endoplasmic reticulum stress, nuclear factor-κB dysregulation, and interferon production. The clinical manifestations include periodic fever with various skin findings such as neutrophilic urticarial dermatosis, or vasculitic lesions. Some SAID cases stem from immunodeficiency or allergic reactions related to monogenic mutation. The diagnosis of SAIDs is based on clinical findings of systemic inflammation and genetic confirmation, and have to exclude infections or malignancies. Moreover, a genetic study is essential for clinical features to be suspect SAID with or without a family history. Treatment is based on understanding the immunopathology of SAID, and targeted therapy to control disease flares, reduce recurrent acute phases and prevent serious complications. Diagnosing and treating SAID requires understanding its comprehensive clinical features and pathogenesis related to genetic mutation.