This review will offer an overview of the mechanistic pathways of chronic pain associated with musculoskeletal disorders (MSDs). Traditional electrophysiological pain pathways of these injuries will be reviewed. In addition, recent research efforts in persistent pain have characterized a cascade of neuroimmunologic events in the central nervous system that manifests in pain behaviors and neurochemical nociceptive responses. Physiologic changes in the central nervous system will be covered as they pertain to the interplay of these two areas, and also as they focus on MSDs and injuries. One such injury leading to persistent pain is radiculopathy, which results from nerve root compression or impingement and leads to low back pain. This painful syndrome will be used as an example to provide a context for presenting immune mechanisms of chronic pain and their relationship to injury. Measures of injury biomechanics are presented in the context of the resulting pain responses, including behavioral sensitivity, local structural changes, and cellular and molecular changes in the CNS. Lastly, based on these findings and others, a discussion is provided highlighting areas of future work to help elucidate methods of injury diagnosis and development of therapeutic treatments.