The neuropathy associated with diabetes mellitus is arguably the most common peripheral neuropathy in the developed world. It can be classified into symmetrical and asymmetrical forms. The symmetrical form is predominantly sensory and autonomic, whereas the asymmetrical form can be sensory, or motor, or both, and can affect individual cranial or peripheral nerves. Pathologic and electrophysiologic studies indicate that the symmetrical polyneuropathy is characterized by a distally accentuated loss of myelinated and unmyelinated axons. The multifocal nature of the axonal degeneration and its association with vascular disease in the same pathologic specimens strongly suggest an ischemic cause involving the endoneurial microvascular circulation. The underlying biochemical abnormality appears to be the production of advanced glycosylated end products (AGEPs), in the presence of chronic hyperglycemia, which accumulate on endothelial proteins, causing basement membrane thickening and endothelial cell change. This produces multifocal vascular disease that, in turn, reduces nerve blood flow, causing endoneurial hypoxia and generating oxygen free radicals. Multifocal ischemic neuronal damage results. Currently, there is no accepted treatment, although long-term control of hyperglycemia is beneficial. Symptomatic relief of the burning pain is the most vexing therapeutic problem; tricyclic antidepressants and anticonvulsants have been used alone and together with varying success.