Immune-mediated tissue destruction or disregulation is the cause of multiple common, as well as rare, endocrine disorders including type 1 diabetes, Graves' disease, Hashimoto thyroiditis, and Addison's disease. Each of these disorders can be divided into a series of stages beginning with genetic susceptibility, environmental triggering events, and active autoimmunity, followed by metabolic abnormalities with overt disease. Common genetic susceptibility is suggested by the clustering of a series of disorders in the same individual and his or her family. A major portion of the genetic susceptibility lies in the HLA region, but for several disorders, mutation of transcription factors underlies disease susceptibility (eg, X-linked polyendocrinopathy, immune deficiency and diarrhea, and autoimmune polyendocrine syndrome type 1). With improving immunogenetic and pathogenic understanding, type 1A diabetes is now predictable, and excellent autoantibody screening assays are available. This knowledge, combined with studies in animal models, has led to trials for the prevention of diabetes. In addition, aberrant immunologic reactions (eg, insulin autoantibodies after insulin therapy, Graves' disease after monoclonal anti-T-cell therapy in multiple sclerosis) can complicate standard and experimental therapies. We therefore believe that an understanding of the immunogenetics and immunopathogenesis of endocrine disorders can aid in the prevention of morbidity and mortality for these related diseases. (J Allergy Clin Immunol 2003;111:S624-36.)