Injured nerves regenerate slowly and often over long distances. Prolonged periods for regenerating nerves to make functional connections with denervated targets prolong the period of isolation of the neurons from the target (chronic axotomy) and of the denervation of Schwann cells in the distal nerve pathways (chronic denervation). In an animal model, we demonstrated that prolonged axotomy and chronic denervation severely reduce the regenerative capacity of neurons to less to 10%. Concurrent reduction in neurotrophic factors, including brain- and glial-derived neurotrophic factors (BDNF and GDNF) in axotomized neurons and denervated Schwann cells, suggest that these factors are required to sustain nerve regeneration. Findings that exogenous BDNF and GDNF did not increase numbers of neurons that regenerate their axons in freshly cut and repaired rat nerves, but "did" increase the numbers significantly after chronic axotomy, are consistent with the view that there is sufficient endogenous neurotrophic factor supply in axotomized motoneurons and denervated Schwann cells to support nerve regeneration but that the reduced supply must be supplemented when target reinnervation is delayed. In addition, findings that BDNF is essential for the effectiveness of brief low frequency electrical stimulation in promoting nerve growth, provides further support for a central role of BNDF in motor nerve regeneration. Learning outcomes: Readers of this article will gain an understanding of the basis for poor functional outcomes of peripheral nerve injuries, even when surgical repair is possible. (Contains 3 figures.)