This chapter summarizes the experimental findings and observations based on the nonobese diabetic (NOD) mouse model and discusses the pathogenesis and the etiology of autoimmune diabetes. To elucidate the etiology of insulin-dependent diabetes mellitus (IDDM), several animal models have been developed, including experimentally induced and spontaneously developing models. One is low-dose streptozocin-induced diabetes. A high dose of streptozocin destroys completely pancreatic β cells but not α and δ cells, resulting in acute diabetes. Multiple injections of subdiabetogenic doses of streptozocin can also induce diabetes a few weeks after treatment. In the latter case, mononuclear infiltration in and around pancreatic islets is observed. IDDM in NOD mice is also immunologically mediated. IDDM in BB rats and NOD mice is very similar to the disease in humans. The availability of a large number of data and materials in mouse genetics and immunology has accelerated the use of NOD mice by diabetologists and immunologists who are interested in the pathogenesis of IDDM and the mechanism of autoimmunity. Several important findings obtained from studies on NOD mice have provided new insights into the immunological and genetic control of IDDM. The development of IDDM in NOD mice is divided roughly into two phases: initiation of autoimmune insulitis and promotion of islet destruction and overt diabetes.