Animal models of type 1 diabetes provide excellent tools for investigators to evaluate the pathogenesis, metabolic effects, and complications of type 1 diabetes. These models have many features of human type 1 diabetes with some important exceptions that will be pointed out in this chapter. The animal models include both spontaneous disease models as well as induced diabetes such as streptozotocin-induced diabetes. One of the most widely used spontaneous disease models is the inbred nonobese diabetic (NOD) mouse model. Investigators in Japan derived the NOD mouse line during inbreeding studies to produce a cataract-prone strain, designated CTS (1). This spontaneous cataract mouse model was derived from the outbred ICR mouse line. During their studies, they noted that a mouse had spontaneous hyperglcemia. They did brother-sister matings of some of the cataract-free mice that had either high or low fasting plasma glucoses. Paradoxically, the diabetic mice were derived from the low-fasting-glucose line and a diabetes-resistant mouse, NON, was derived from the high-fasting-glucose line. The NON mouse, genetically similar to the NOD mouse, served as a nondiabetic control mouse strain. The NOD mice have been used widely as a mouse model of type 1 diabetes for the past 20 yr. These mice have a T-cell-mediated diabetes and share many of the classic features of type 1 diabetes, including the presence of lymphocytic infiltration of the islets present prior to the onset of clinical diabetes, insulinopenia, hyperglycemia, polyuria, and weight loss (1).