Chronic musculoskeletal (MSK) pain is a leading cause of disability affecting patients and healthcare systems worldwide. Its burden is expected to rise sharply due to the aging global population. Given that chronic MSK pain is the most common condition treated by chiropractors daily, chiropractic is ideally positioned to assume a unique leadership role in the future health delivery system of managing this growing clinical challenge. Central sensitization (CS) is linked to an increasing number of chronic pain conditions characterized by increased sensory, sympathetic, and motor excitability. Accumulating evidence suggests that spinal manipulation may achieve its therapeutic benefits by modulating CS, thereby making it a potentially effective non-invasive approach to treating and managing chronic MSK pain. This review aims to provide a discussion of some of the scientific foundations underpinning the pathophysiologic mechanisms of chronic MSK pain and spinal manipulative therapy, as they relate to the contemporary neurophysiologic paradigm of chiropractic medicine and practice.This paper is one of seven in a series exploring contemporary perspectives on the application of the evidence-based framework in chiropractic care. The Evidence Based Chiropractic Care (EBCC) initiative aims to support chiropractors in their delivery of optimal patient-centred care. We encourage readers to review all papers in the series.