Diabetes mellitus is a common cause of peripheral nervous system disorders that manifest in a variety of clinical forms, many of which are often misdiagnosed. Over the past two decades, our understanding of the pathophysiology of diabetic nerve injury has improved remarkably through the elucidation of the important roles of the polyol pathway of glucose metabolism, oxidative injury, advanced glycosylation end-products, vascular insufficiency, and other mechanisms. A large number of clinical treatment trials based upon this abundant scientific data have met with limited success, but ongoing and future trials offer promise for more dramatic success in treating this common cause of morbidity and mortality in the diabetic population.