Despite improvements in the ongoing care of individuals with insulin-dependent diabetes, the disease continues to produce significant morbidity and mortality, especially early in life, in individuals developing insulin-dependent diabetes in childhood or adolescence. In order to have a major impact on disease outcome, the best therapeutic approach is disease prevention. Because insulin-dependent diabetes results from autoimmune pancreatic beta cell destruction, the disease may be amenable to immunological intervention with immunotherapy. This is particularly exciting as we develop tools, such as islet cell autoantibody determinations, that allow diagnosis of individuals prior to clinical presentation. It is during this time-period when immune manipulation may be most efficacious in preventing further beta cell destruction, and otherwise eventual insulin dependence. As such trials are highly experimental, they must be conducted only in research centers staffed by physicians and scientists with expertise in diabetes, autoimmunity, and immunology.