Insulin-dependent diabetes mellitus (IDDM) is a T-cell mediated autoimmune disease, which results in the destruction of the islet beta-cells. The major histocompatibility complex (MHC) encodes the major susceptibility gene in IDDM. The concordance rate for diabetes in identical twins is 30-50% and in inbred animal models of disease the incidence rate is 20-80%. These results emphasize a role for environmental factors in the disease process. It has long been suggested that IDDM in humans may be caused by-viral infections. While considerable progress has been made in defining the genetics of IDDM, our understanding of the role of environmental factors, which might provide a more direct approach to therapy is considerably lacking. We suggest that (1) the density and affinity of epitopes derived from microbial antigens that bind to MHC molecules; (2) their cross-reactivity with beta-cell antigens; and (3) the nature of immunoregulatory cytokines induced by the microbial infections are the primary factors in the induction of either effector or protective T cells in IDDM.