The autoimmune polyglandular syndromes—a group of syndromes comprising a combination of endocrine and nonendocrine autoimmune diseases—differ in their component diseases and in the immunologic features of their pathogenesis. One of the three main syndromes, type 1 autoimmune polyglandular syndrome (APS-1), has a unique pathogenic mechanism owing to mutations in the autoimmune regulator (AIRE) gene, which results in the loss of central tolerance—a process by which developing T cells with potential reactivity for self-antigens are eliminated during early differentiation in the thymus. Patients with IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) syndrome harbor mutations in the forkhead box P3 (FOXP3) gene in regulatory T cells, which leads to severe autoimmunity and immune deficiency. Although both of these disorders are rare, their well-defined mechanisms of disease provide a basis for the understanding of the more common condition, APS-2. In this syndrome, alleles of human leukocyte antigens (HLAs) determine the targeting of specific tissues by autoreactive T cells, which leads to organ-specific autoimmunity as a result of this loss of tolerance. Non-HLA genes also contribute to autoimmunity in APS-2 and, depending on the polymorphism, potentially predispose to a loss of tolerance or influence which organ is specifically targeted. This Review discusses the genetic basis of APS-1, APS-2 and IPEX syndrome, with an emphasis on the mechanisms of autoimmunity and presents currently available therapies to treat their underlying autoimmune disorders.