Peripheral nerve injuries, especially those with complete transection of major nerves, create significant morbidity including debilitating pain, loss of protective haptic feedback, and impaired volitional control of musculature. The societal burden and cost of medical care for these injuries are enormous, with estimates in the United States alone in excess of 70 million per year. In clinical scenarios with a segmental nerve gap where end-to-end coaptation without tension is not possible, a "bridge" or scaffold must be interposed to facilitate communication between the proximal and distal stumps to facilitate organized growth following Wallerian degeneration. A multitude of constructs have been created and studied to facilitate this regeneration. Among the three overall types of bridge employed in contemporary clinical care-conduit/scaffold, allograft, and autograft-each has significant downsides ranging from limited successful nerve ingrowth to donor site morbidity. Despite the tremendous work over the last 150 years in nerve biology and medical technology for the treatment of peripheral nerve injury, the biological processes governing nerve regeneration remain incompletely understood. Especially in cases of long segmental gaps, there remains room for significant improvement. Ongoing studies have identified several promising modalities for nerve scaffolds to facilitate more efficient and effective neuronal outgrowth but still require further investigation. Here, we review contemporary paradigms in the treatment of segmental nerve injuries with interposing scaffolds and reexamine nerve physiology, regulatory programs in nerve regeneration, and strategic targets for neurogenic pathways that may facilitate novel treatment modalities.