It has been 30 years since the discovery of the nonobese diabetic (NOD) mouse (1974) at the Shionogi Research Laboratories in Osaka, Japan (Hanafusa et al., 1994). In this time the NOD mouse has greatly advanced our knowledge of the pathogenesis of type 1 diabetes (T1D) and helped to establish the etiology as autoimmune. With the development of spontaneous diabetes, the NOD mouse shares many pathological features with human T1D making it a valuable model for research. Disease is associated with specific major histocompatibility complex (MHC) alleles, anti-insulin autoantibodies precede diabetes, and b-cell–specific cellular responses have been well documented. Some important advantages of the NOD mouse autoimmune model for diabetes include access to the pancreas at preclinical stages in the immunopathology, the ability to breed and genetically manipulate animals, and the capacity to employ intervention strategies at preclinical and postclinical disease stages. There have been a number of ‘‘major breakthroughs’’over the past 30 years that have helped advance our knowledge into the pathogenesis of T1D. This chapter starts by discussing the origin of the NOD mouse, the pathogenesis of diabetes, and the role of the immune cells in pathogenesis and then discusses some of the important discoveries that have facilitated and expanded our understanding of both immunity and autoimmunity.