Peripheral nerve regeneration presents a significant clinical challenge and the current state of the art using autografts to repair long peripheral nerve gaps is unsatisfactory. In this manuscript, the analytical framework that determines the fate of grafts (autografts or biomaterial-based grafts) is discussed. Also outlined are parameters and variables that might be manipulated to enhance the efficacy of scaffolds designed for peripheral nerve regeneration. The importance of using appropriate animal models and outcome measures in evaluating biomaterials-based scaffolds or other engineered constructs suitability for bridging peripheral nerve gaps is highlighted.