Experimental studies have provided multiple mechanisms for the development of diabetic neuropathy, yet very few findings have been replicated in patients. Hyperglycemia mediated nerve damage may begin very early even prior to overt diabetes as evidenced by several recent studies in patients with impaired glucose tolerance. Polyol pathway abnormalities have been exhaustively explored in animals, but studies in man are limited and inconsistent and hence not surprisingly, clinical trials with aldose reductase inhibitors have consistently failed. Glycation is widespread and may induce a range of structural and functional changes and glycation inhibitors are being actively developed. Both large and small vessel disease have been implicated in diabetic neuropathy and treatment with ACE inhibitors has shown some benefit. Growth factors may be important in maintaining both the vascular and neuronal phenotype. Thus a range of neurotrophic and vascular growth factors have entered phase III clinical trials for human diabetic neuropathy recently.