The characterization of patients with recurrent inflammatory syndromes into distinct clinical phenotypes provided early clues to the mode of inheritance of these conditions and facilitated the subsequent identification of causative gene mutations. The prototype autoinflammatory syndrome, familial Mediterranean fever, is characterized by self-limiting episodes of localized inflammation. Hallmarks of the classical autoimmune response are largely absent. The use of positional cloning techniques led to the identification of the causative gene, MEFV, and its product pyrin. This previously unrecognized protein plays an important role in modulating the innate immune response. Cryopyrin, the protein encoded by CIAS1, is mutated in a spectrum of autoinflammatory conditions, the cryopyrinopathies. In response to a wide range of potential pathogens, it forms a macromolecular complex termed the "inflammasome," resulting in caspase-1 activation and subsequent release of the active proinflammatory cytokine interleukin-1beta (IL-1beta). The role of an established biochemical pathway in regulating inflammation was uncovered by the discovery that the hyperimmunoglobulin D with periodic fever syndrome (HIDS) results from mutations in MVK, which encodes an enzyme in the isoprenoid pathway. The discovery that mutations in the gene encoding tumor necrosis factor (TNF) receptor 1 (TNFR1) cause a proinflammatory phenotype was unanticipated, as it seemed more likely that such mutations would instead have resulted in an immunodeficiency pattern. This review describes the clinical phenotypes of autoinflammatory syndromes, the underlying gene mutations, and current concepts regarding their pathophysiology.