The polyglandular autoimmune syndromes (PAS) comprise a wide spectrum of autoimmune disorders. There exist a juvenile (PAS I) and an adult type (PAS II). The nature of PAS has been based on the presence of lymphocyte infiltration in the affected gland, organ-specific antibodies in the serum, cellular immune defects and an association with the human leucocyte antigen (HLA) DR/DQ genes or immune response genes. Autoantibodies to the various endocrine and non-endocrine tissues not only offer a diagnostic clue to the autoimmune nature of diseases but also can be used to identify asymptomatic individuals who are at risk of developing other component diseases of the syndrome. Although target tissues or glands differ, several common threads link the diseases of PAS. A defect resides in one of the genes of the HLA locus which, in concert with other gene(s), results in susceptibility. Genetic susceptibility is necessary but not sufficient to produce the disorder. This is illustrated by the lack of 100% concordance of disease in identical twins. Genetic testing may identify patients with PAS I, but not those with PAS II. For PAS II, susceptibility genes are known which increase the risk for developing autoimmune disorders, but must not be causative. These are certain HLA genes, the cytotoxic T-lymphocyte antigen (CTLA-4) gene, and the protein tyrosine phosphatase non-receptor type 22 (PTPN22) genes on chromosomes 6, 2, and 1, respectively. When the genetic defects and environmental influences of organ-specific autoimmunity are better understood, it may be possible to devise specific replacement or corrective therapies. Given the similar features of many of the organ-specific autoimmune disorders, it is likely that if immunotherapeutic modalities are successful in one disease, they may be of benefit in related disorders.