Neuropathy is a common and devastating complication of diabetes that contributes to mortality in most cases. Multiple factors are thought to play a major role in the pathogenesis of diabetic neuropathy, including alterations in the endoneural metabolism, defective neurotrophic factors, reduced nerve blood supply, and immune mechanisms. Studies of endoneural metabolism and nerve blood-flow alterations have focused on oxidative stress, the polyol pathway, advanced glycation, protein kinase C, and impaired essential fatty acid metabolism. Although many experimental and clinical studies have been performed to determine the most optimal strategy for preventing and treating diabetic neuropathy, tight glycemic control is the mainstay of therapy. In this article, the proposed pathophysiologic mechanisms and therapeutic approaches in diabetic neuropathy are reviewed and discussed with the relevant literature.