Insulin-dependent diabetes mellitus places a major burden on both affected individuals and society because of its high morbidity and mortality rates and financial costs. That the disease occurs in genetically susceptible individuals as a result of an immunologically mediated process thought to be triggered by environmental factors probably operating in early childhood is well established. Enhanced knowledge of the immunopathogenesis, genetics, and natural history of insulin-dependent diabetes mellitus in nonobese diabetic mice and humans has enabled investigators to better predict disease onset and design therapies aimed at its prevention. Major national and international multicenter trials are currently in progress, engendering cautious optimism that the disease may safely be prevented.