Although the epidemiology of type 2 diabetes (T2D) has been well described, there is much about the disease that remains unclear. For example, lifestyle factors-including increased body weight with visceral fat deposition and insufficient physical activity-are thought to be primary contributors to the adverse changes in the metabolism of muscle and fat cells that comprise the first stage of the disease. However, the precise mechanisms underlying these initial alterations are incompletely understood. Other, less obvious questions relate to the presence of sex differences in the development and health consequences of T2D, the etiological role of the central nervous system ("stress"), and the potential evolutionary origins of T2D susceptibility. Some of these issues can be resolved by further study of human populations. However, many questions can be answered only through the kinds of controlled prospective studies that are conducted with appropriate animal models. The use of such models can be an invaluable part of an overall strategy designed to elucidate the mechanisms underlying the development of T2D, understand the natural history of the disease, identify targets for therapy, and evaluate interventions. Current evidence indicates that no single animal model replicates the development of human T2D in all of its details. Nonetheless, the existing models (e.g., naturally occurring and genetically modified rodents, cats, pigs, and nonhuman primates) offer researchers a rich array of opportunities to investigate the myriad complexities of T2D. The individual contributions comprising this issue of ILAR Journal review the research that has been conducted on many of these animals.