Type 2 diabetes mellitus (TTDM) is characterized by progressive loss of glucose control through multifactorial mechanisms. The search for an understanding of TTDM has relied on animal models since the realization of the importance of the pancreas in controlling plasma glucose concentration. Rodent models of TTDM are developed to express hyperglycemia and not islet degeneration per se. Degeneration of the islets of Langerhans with beta-cell loss is secondary to insulin resistance and is regarded as the more important lesion. Despite this, differences between models are seen in the development and progression of islet degeneration. Assessing the differences between the models is important to appreciate the various aspects of TTDM and understand their advantages as well as their deficiencies. Relevant animal models of TTDM provide opportunities to investigate important physiological and cell biological processes that may ultimately lead to development of targeted therapies. This article reviews the importance, advantages, and limitations of rodent models of TTDM in relation to the histopathological changes that characterize islet degeneration. Pathophysiological mechanisms that contribute to islet degeneration are also discussed and are placed into the context of changes in islet histological appearances.