The high comorbidity of panic disorder and depression might be anticipated on epidemiologic grounds alone. Both are common disorders with a characteristically chronic course, increasing the probability that a given patient with one disorder will develop the other. Symptoms of anxiety are highly prevalent among depressed patients; however, not all such symptoms represent an actual comorbid anxiety disorder. Conversely, about 50% of patients with panic disorder ultimately experience an episode of major depression. The comorbidity of panic disorder and depression has significant and potentially ominous prognostic implications; the high rate of suicide attempts observed in panic disorder are further exacerbated by the presence of a comorbid depression. Panic disorder and depression share well-defined disturbances in hypothalamic-pituitary-adrenal axis function, serotonergic neurotransmission, and growth hormone response to pharmacologic challenge. In addition, most of the available medications used to treat depression are also first-line therapy for panic disorder. Although initial studies suggested that patients with comorbid panic disorder and depression have a poorer treatment outcome, recent data show similar outcomes for patients with both disorders and those with panic disorder uncomplicated by depression.