Type 1A (immune-mediated) diabetes mellitus is now a predictable disorder, and its onset can be prevented or delayed in animal models with therapies that include the administration of islet autoantigens. To date, therapies that can delay but not prevent anti-islet autoimmunity in animal models have not delayed the development of the disease in humans. Basic and physician scientists are addressing a number of barriers to the development of effective preventive therapy, with important recent progress in monitoring immune responses to beta-cell-specific autoantigens. It is likely that optimal prevention of type 1A diabetes mellitus will depend on the ability to abrogate pre-existing autoimmunity directed at beta-cell-specific peptides.