Type 1A diabetes is a chronic autoimmune disease usually preceded by a long prodrome during which autoantibodies to islet autoantigens are present. These antibodies are directed to a variety of antigens, but the best characterized are glutamic acid decarboxylase-65, insulinoma-associated antigen-2, and insulin. We hypothesize that the natural history of type 1A diabetes can be represented by several stages, starting from genetic susceptibility and ending in complete beta-cell destruction and overt diabetes. Type 1A diabetes probably results from a balance between genetic susceptibility and environmental influences. In both humans and animal models, the major determinants of the disease are genes within the major histocompatibility complex. The next best-characterized susceptibility locus is the insulin gene, the variable nucleotide tandem repeat locus. This gene affects the expression of insulin in the thymus and thus may play a role in the modulation of tolerance to this molecule. In a subset of genetically susceptible individuals, the activation of autoimmunity may be triggered by environmental factors such as viruses and/or diet. However, no conclusive association has been established between type 1A diabetes and specific environmental triggers. In this review, we provide evidence that insulin has a fundamental role in anti-islet autoimmunity.