In 1986, enough information was available based on studies by investigators from four continents to propose a model of the pathogenesis of Type 1A diabetes. The model divided pathogenesis into a series of stages with the proposal that insulin-dependent diabetes was a chronic autoimmune disorder. Long-term studies of non-diabetic identical twins of patients with Type 1A diabetes indicated that chronic loss of the ability to secrete insulin preceded the onset of diabetes in the presence of both genetic susceptibility and expression of anti-islet autoantibodies. It is now clear that the great majority of individuals who develop Type 1A diabetes show both immunologic and metabolic abnormalities before the development of overt diabetes. A combination of detection of anti-islet autoantibodies, genetic characteristics and metabolic abnormalities can now be used to predict Type 1A diabetes as well as approximate timing of diabetes onset. This knowledge has led to clinical trials on the prevention of Type 1A diabetes that hope to harness a remarkable increase in basic immunologic knowledge and a new generation of immunomodulatory therapies. Despite this increase in knowledge of the natural history of Type 1A diabetes and pathogenesis in animal models, much remains to be defined to allow efficient and successful disease prevention.