For patients with chronic pain, the experience of pain is intimately linked with psychologic distress. Epidemiologic studies indicate that depression is a common comorbidity accompanying chronic pain states. Longitudinal studies also suggest that depression can predict the emergence of chronic pain in selected populations. Emerging evidence suggests numerous pathophysiologic mechanisms that underlie the coexistence of depression and chronic pain states. Comorbid depression can complicate the presentation, clinical course, and response to treatment of patients with chronic pain. The literature reviewed herein focuses on treatment approaches applicable to chronic, nonmalignant pain states predominantly. Although antidepressants offer advantages in simultaneously producing pain relief and mitigating depression, not all antidepressants share equal efficacy; those with noradrenergic and serotonergic influences seem to fare better than agents with single neurotransmitter influences. Treatment of depression may be essential to fully enlist the patient with chronic pain in comprehensive pain management and rehabilitative approaches. Management plans of patients with chronic pain can be designed with specific individual patient needs in mind, and may involve concurrent use of antidepressants, analgesics, and psychotherapeutic approaches.