Autoimmunity is a complex process that likely results from the summation of multiple defective tolerance mechanisms. The NOD mouse strain is an excellent model of autoimmune disease and an important tool for dissecting tolerance mechanisms. The strength of this mouse strain is that it develops spontaneous autoimmune diabetes, which shares many similarities to autoimmune or type 1a diabetes (T1D) in human subjects, including the presence of pancreas-specific autoantibodies, autoreactive CD4+ and CD8+ T cells, and genetic linkage to disease syntenic to that found in humans. During the past ten years, investigators have used a wide variety of tools to study these mice, including immunological reagents and transgenic and knockout strains; these tools have tremendously enhanced the study of the fundamental disease mechanisms. In addition, investigators have recently developed a number of therapeutic interventions in this animal model that have now been translated into human therapies. In this review, we summarize many of the important features of disease development and progression in the NOD strain, emphasizing the role of central and peripheral tolerance mechanisms that affect diabetes in these mice. The information gained from this highly relevant model of human disease will lead to potential therapies that may alter the development of the disease and its progression in patients with T1D.