The burden of mental illness has been underestimated worldwide. Depression was the fourth leading cause of disease burden in the world in 1990 and is projected to be the second leading cause of disability by 2020. It is a leading cause of morbidity and mortality in the United States, costing billions of dollars annually in direct and indirect medical costs and losses in productivity. Patients with major depressive disorder (MDD) may experience both psychological and medical complaints, including somatic sensations or pain. Some antidepressants have been shown to treat chronic pain syndromes, but despite the variety of antidepressants available in the United States, only 65-70% of patients respond to initial antidepressant treatment. Treatments are limited by delayed onset of antidepressant effects, side effects, partial response, and treatment resistance. Duloxetine, approved by the U.S. Food and Drug Administration for the treatment of MDD, is a reuptake inhibitor at serotonergic and noradrenergic neurons and appears to have low affinity for other neurotransmitter systems. In clinical trials, duloxetine was effective for the treatment of MDD and was well tolerated. Further study is needed to compare its efficacy with that of other antidepressants, to clarify effects on somatic symptoms, and to assess potential adverse cardiovascular and sexual side effects. Duloxetine is also approved for the management of diabetic peripheral neuropathic pain and is under investigation for the treatment of stress urinary incontinence in women.