Current interventions used in musculoskeletal rehabilitation are in largely directed by a biomedical model where peripheral structural injury is thought to be the sole driver of the disorder. There are however neurophysiological changes across different areas of the peripheral and central nervous system including peripheral receptors, dorsal horn of the spinal cord, brain stem, sensorimotor cortical areas and in the meso-limbic and prefrontal areas associated with chronic musculoskeletal disorders including chronic low back pain, osteoarthritis, and tendon injuries. These neurophysiological changes appear to be not only a result of peripheral structural injury but play a role in the pathophysiology of chronic musculoskeletal disorders. Neurophysiological changes are consistent with a bio-psycho-social formulation reflecting the underlying mechanisms related to sensory and motor findings, psychological traits, and perceptual changes associated with chronic musculoskeletal conditions. These changes therefore have significant implications in the clinical manifestation, pathophysiology and for rehabilitative treatment of chronic musculoskeletal disorders. Musculoskeletal rehabilitation professionals have at their disposal tools to address these neuroplastic changes including top down cognitive based interventions (such as education, cognitive behavioral therapy, mindfulness meditation and motor imagery), and bottom up physical interventions (such as motor learning, peripheral sensory stimulation, and manual therapy) that induce neuroplastic changes across distributed areas of the nervous system and impact outcomes in patients with chronic musculoskeletal disorders. Furthermore, novel approaches like the use of transcranial direct current stimulation and repetitive transcranial magnetic stimulation may also be used to assist in renormalizing neurological function. Comprehensive treatment addressing peripheral structural injury as well as neurophysiological changes occurring across distributed areas of the nervous system may aid in improving outcomes in patients with chronic musculoskeletal disorders.