Spontaneous insulin-dependent diabetes mellitus in the rat is a multigenic, multifactorial condition. We have identified three phenotypic characteristics of the syndrome. The first is an association with the RT1u haplotype of the rat major histocompatibility complex. A single RT1u haplotype is permissive, although the relative risk of developing the disease is increased when the animal is homozygous. An immunoregulatory defect, which is characterized phenotypically by a severe T lymphocyte depletion, behaves as if it were regulated by a single autosomal recessive gene which segregates independently of the RT1. The third phenotype characteristic is the presence of lymphocytic infiltration of the pancreas. The genetics of this characteristic have not been delineated, although there is evidence that it behaves as a dominant. In addition to the requirement for several genes, environmental events are important for full expression of the syndrome.