Neuropathy remains a major complication of diabetes and there is no approved treatment that prevents its progression or alleviates the associated symptoms. Animal models of diabetic neuropathy are hampered by their short life span, which precludes the development of overt structural pathology, and they are best viewed as exhibiting early metabolic, neurochemical, and functional indices of nerve disorders that may predict progression to overt diabetic neuropathy. In this context, diabetic animals have use in both establishing potential etiologic mechanisms and for screening novel therapeutic agents. Treatment strategies are evolving in concert with a developing understanding of how hyperglycemia causes nerve dysfunction and recent or ongoing clinical trials are investigating this rational approach to drug design. It is only by the successful demonstration of clinical efficacy of a compound developed by this approach that the use of animal models of diabetic neuropathy can be validated.