There has been an expansion of the autoinflammatory syndromes due to the discovery of new diseases related to mutations in genes regulating the innate immune system and the knowledge gained from these diseases as applied to more common nongenetic inflammatory conditions. Autoinflammatory syndromes are characterized by unprovoked (or triggered by minor events) recurrent episodes of systemic inflammation involving various body systems, which are often accompanied by fever. Inflammation is mediated by polymorphonuclear and macrophage cells through cytokines, particularly interleukin-1. This article reviews the clinical approach to patients with suspected autoinflammatory syndromes, several of the main and new (mostly genetics) syndromes, advances in treatment, and prognosis.