Traumatic nerve injuries result in devastating loss of neurologic function with unpredictable functional recovery despite optimal medical management. After traumatic nerve injury and denervation, regenerating axons must traverse a complex environment in which they encounter numerous barriers on the way to reinnervation of their target muscle. Outcomes of surgical intervention alone have unfortunately reached a plateau, resulting in often unsatisfactory functional recovery. Over the past few decades, many improvements were developed to supplement and boost the results of surgical repair. Biological optimization of Schwann cells, macrophages, and degradation enzymes have been studied due to the key roles of these components in axonal development, maintenance and response to injury. Moreover, surgical techniques such as nerve grafting, conduits, and growth factor supplementation are also employed to enhance the microenvironment and nerve regeneration. Yet, most of the roadblocks to recovery after nerve injury remain unsolved. These roadblocks include, but are not limited to: slow regeneration rates and specificity of target innervation, the presence of a segmental nerve defect, and degeneration of the target end-organ after prolonged periods of denervation. A recognition of these limitations is necessary so as to develop new strategies to improve functional regeneration for these life changing injuries.