Fibromyalgia is a chronic musculoskeletal pain condition of unknown etiology that predominantly affects women. Lifetime mood and anxiety disorders are common in patients with fibromyalgia and affect the course and severity of fibromyalgia. Recent fibromyalgia clinical trials have included clinical assessments to identify comorbid psychiatric disorders and determine the impact of comorbidity on treatment response. Options for the treatment of fibromyalgia patients with comorbid major depressive disorder or anxiety disorders include antidepressants with dual effects on serotonin and norepinephrine (eg, venlafaxine, duloxetine), which reduce pain in patients with fibromyalgia and have antidepressant and anxiolytic activity. Other possible treatments for anxiety or sleep disturbances associated with fibromyalgia include the alpha-2-delta ligands (eg, pregabalin, gabapentin) that reduce pain in fibromyalgia patients, have anxiolytic effects, and enhance slow-wave sleep. Antidepressants or alpha-2-delta ligands should be combined with established mood stabilizers in patients with comorbid fibromyalgia and bipolar disorder. There is also evidence to support exercise and cognitive-behavioral therapy in the treatment of fibromyalgia and mood or anxiety disorders. Many patients would likely benefit from combinations of pharmacologic and nonpharmacologic treatments.