Since their discovery in the 1950s, neurotrophic factors have raised expectations that their clinical application to neurodegenerative diseases might provide an effective therapy for what are now untreatable conditions. Nerve growth factor (NGF) was the first neurotrophic factor to be discovered and was one of the earliest to proceed to clinical trials. NGF, which is selectively trophic for small fiber sensory and sympathetic neurons, was selected as a potential theraphy for diabetic polyneuropathy becaus of the serious consequences associated with degeneration of those neuronal populations in this condition. In addition, evidence shows that reduced availability of NGF may contribute to the pathogenesis of diabetic neuropathy, and animal models of neuropathy respond to the exogenous administration of NGF. Two sets of phase II clinical trails suggested that recombinant human NGF (rhNGF) administration was effective at ameliorating the symptoms associated with both diabetic polyneuropathy and HIV-related neuropathy. These early studies, however, revealed that painful side effects were dose limiting for NGF. A large-scale phase III clinical trail of 1019 patients randomized to receive either rhNGF or palcebo for 48 weeks failed to confirm the earlier indications of efficacy. Among the explanations offered for the discrepancy between the two sets of trails was a robust palcebo effect, inadequate dosage, different study populatioms, and changes to the formulation of rhNGF for the phase III trail. As a result of the phase III outcome, Genentech has decided not to proceed with further development of rhNGF.