Pain is one of the most important and challenging consequences of musculoskeletal disorders. This article examines the role of central nervous system structures in the physiology of pain. It also describes the neuromatrix, a construct that provides a framework for understanding the interaction between physiologic mechanisms and psychosocial factors in the development and maintenance of chronic pain. This construct suggests that behavioral and psychologic interventions may alter the pain experience primarily through their effects on emotional states and cognitive processes. The literature on cognitive-behavioral interventions for patients with rheumatoid arthritis and osteoarthritis indicates that they are well-established treatments for these disorders. However, the efficacy of these interventions for patients with fibromyalgia has not been established. It is anticipated that the development of valid measures of readiness for behavioral change may allow investigators to identify the patients with musculoskeletal disorders who are most likely to benefit from cognitive-behavioral intervention.