The term ‘regional interdependence’ or RI has recently been introduced into the vernacular of physical therapy and rehabilitation literature as a clinical model of musculoskeletal assessment and intervention. The fundamental premise of this model is that apparently unrelated impairments in remote anatomical regions of the body may contribute to and be connected with a patient’s primary report of symptoms. The clinical implication of this premise is that interventions directed at one region of the body will often have effects at remote and seemingly unrelated areas. The formalized concept of RI is relatively new and was originally derived in an inductive manner from a variety of earlier publications and clinical observations. However, recent literature has provided additional support to the concept. The authors’ primary purpose in this article was to further refine the operational definition for the concept of RI, examine supporting literature, discuss possible clinically relevant mechanisms, and conclude with a discussion of the implications of these findings on clinical practice and research.