Many millions of Americans suffer chronic medical conditions complicated by both depression and pain. Chronic pain disorders may be classified as being caused by one or more mechanisms, such as nociceptive (inflammatory), neuropathic (peripheral and central), and myofascial, each associated with a complex substrate of neurophysiologic changes. Specific treatment approaches have been developed for different pain mechanisms. Because all pain sensation is personal and subjective, all pain is affected to some degree by emotional states, and, therefore, by psychosocial factors. Major depression commonly complicates chronic pain and adds to impairment and disability. There is evidence that patients with depression occurring after the onset of chronic pain have the same rates of affective disorders in family members as in the general population, and significantly lower rates than in families of patients with major depression alone. This suggests that it is the stress of living with chronic pain, not personal or family predisposition, that causes depression in these patients. Optimal treatment includes treatment of both pain and depression, together with a focus on symptom control and functional restoration.