Chronic musculoskeletal pain is one of the most intractable clinical problems faced by clinicians and can be devastating for patients. Central pain amplification is perceived pain that cannot be fully explained on the basis of somatic or neuropathic processes and is due to physiologic alterations in pain transmission or descending pain modulatory pathways. In any individual, central pain amplification may complicate nociceptive or neuropathic pain. Furthermore, patients with somatic symptom disorders may have alterations in their psychological or behavioral responses to pain that contribute significantly to the clinical presentation. Genetic, physiologic, and psychological factors associated with central pain amplification are beginning to be understood. One important contributor to chronic pain is perceived stress and stress response systems. We and others have shown a complex relationship between the physiologic stress response and chronic pain symptoms. Unfortunately, treatments for chronic pain are woefully inadequate and often worsen clinical outcomes. Developing new treatment strategies for patients with chronic pain is of utmost urgency. This essay provides a framework for thinking about chronic pain and developing new treatment approaches.