The nonobese diabetic (NOD) mouse is a model of human autoimmune insulin-dependent diabetes mellitus. The NOD mouse also serves as a model for studying complex polygenic diseases because at least fourteen different loci are linked to disease development. The first Idd locus recognized, Idd1, is linked to the major histocompatibility complex (MHC), and its inheritance and expression are a paradigm for the other non-MHC Idd genes. The NOD allele at Idd1 does not behave as a recessive diabetes susceptibility gene, as it was originally thought to be, but instead it acts as a dominant gene with varying degrees of penetrance for the phenotypes of insulitis, a prediabetic inflammatory lesion, and spontaneous diabetes. MHC congenic strains of mice have shown that the NOD MHC is essential but, by itself, not sufficient for developing diabetes. The contributions of non-MHC Idd loci have also been assessed with NOD congenic strains derived by replacing NOD-specific chromosomal segments with those from diabetes-resistant strains of mice. While only partial protection from disease is provided by resistance alleles at single non-MHC Idd loci, epistatic interaction between two of the loci, Idd3 and Idd10, produced nearly complete protection from diabetes. Identifying Idd genes and defining their biologic functions should further our understanding of autoimmune disease pathogenesis and facilitate development of new treatments for diabetes.