Diabetic neuropathy is the most common complication in diabetes. To date, there are few efficacious therapies for this complication. Several groups of drugs have undergone clinical testing, the outcome of which has not yielded convincing benefits. Diabetic neuropathy is a dynamic chronic degenerative disorder with multiple interactive pathogenetic mechanisms complicating the design of biologically-meaningful therapies. New insights into this disorder and the fact that it differs in the two types of diabetes has drawn attention to the etiological effects of insulin/C-peptide deficiency in diabetic neuropathy. Recent data regarding regulation of the aldose reductase gene has fueled new interest in aldose reductase inhibitors. A more downstream metabolic abnormality, oxidative stress, provoked by several mechanisms has become a therapeutic target of great interest. Therefore, despite previous therapeutic failures, there is now a renewed interest and reassessment of old therapies, as well as development of totally new strategies.