There has been a rapid growth in appreciation of the diverse array of neurotrophic factors, growth factors and other biological molecules that have the capacity to support adult neurons and direct reparative processes after injury to the nervous system. Understanding the mechanisms by which these factors operate offers the opportunity to use either the factors themselves or other agents that manipulate relevant signal transduction pathways as therapeutics for a wide range of neurodegenerative diseases, including diabetic neuropathy. In this review, we aim to summarize current knowledge of the extent to which loss of neurotrophic support contributes to the pathogenesis of diabetic neuropathy, present preclinical evidence that supports the potential efficacy of growth factors or their mimetics against indices of diabetic neuropathy and highlight the emerging approaches to manipulating neuronal support mechanisms that show potential for translation to clinical use. Recent advances in directly assessing the progression of nerve damage in diabetic patients will hopefully facilitate renewed clinical evaluation of treatments for degenerative diabetic neuropathy and provide the framework for advancing the potential of growth factors as a therapy for this widespread and currently untreatable condition.