Treatment of peripheral nervous system (PNS) pathology presents intervention challenges to every therapist. Many of the current and future interventions will be directed at restoring the normal anatomy, function, and biomechanical properties of the PNS, restoring normal neural physiology and ultimately patient function and quality of life. Present interventions use mechanical (movement) or electrical procedures to affect various properties of the peripheral nerve. The purpose of this article was to apply basic science to clinical practice. The pathology and accompanying structural and biomechanical changes in the PNS will be presented in three specific areas commonly encountered in the clinic: nerve injury and laceration; compression neuropathies; and neuropathic pain and neural tension dysfunction. The intent is to address possible interventions exploring the clinical reasoning process that combines basic science and evidence-based best practice. The current lack of literature to support any one intervention requires a strong foundation and understanding of the PNSs’ structure and function to refine current and develop new intervention strategies. Current evidence will be presented and linked with future considerations for intervention and research. During this interlude of development and refinement, best practice will rely on sound clinical reasoning skills that incorporate basic science to achieve a successful outcome when treating these challenging patients.