The frequent presentation of patients with panic disorder in medical settings may, in part, be explained by the physical symptoms inherent in panic disorder. However, a number of medical disorders have symptoms that overlap with panic disorder symptoms, and elevated panic disorder prevalence is comorbid with a number of medical illnesses, including respiratory disorders, vestibular dysfunction, and hyperthyroidism and hypothyroidism. The presence of medical comorbidity complicates the identification, presentation, and treatment of panic disorder. In addition, comorbid mood disorders occur commonly and result in greater severity, poorer quality of life, and greater impairment. Recent work suggests that panic disorder occurs more commonly with bipolar disorder than major depressive disorder, resulting in substantial impairment, as well as poorer response to treatment. The implications of mood disorder and its medical comorbidity for the identification and treatment of panic disorder are discussed.