Type I diabetes mellitus appears to result from an insidious immunologic destruction of pancreatic beta-cells in genetically susceptible persons exposed to one or a series of environmental insults. This genetic susceptibility is related to alleles located on the sixth chromosome in the HLA-DR or an adjacent region. With superimposition of a viral or other environmental triggering event, cell-and antibody-mediated events are activated that lead to the specific autorejection of beta-cells and consequent insulin deficiency. Immunosuppressive strategies to impede or halt complete destruction of beta-cells, using cyclosporine, have already been initiated in both animals and humans with diabetes mellitus. Because of the potential toxicity of all current immunosuppressive regimens, such therapies cannot, at this time, be considered for wide-scale use in persons with type I diabetes. Reported inductions, however, of insulin independence in patients with newly diagnosed type I diabetes using cyclosporine or other agents underscore the role of the immune system in the pathogenesis of the disease and highlight the need to develop safer, more specific immunomodulation designed to avoid complete beta-cell destruction.