Comorbidity is the rule with anxiety and depressive disorders. Anxiety and major depressive disorder are often comorbid with each other; these disorders are commonly associated with other psychiatric disorders; and they are frequently found coexisting with long-standing chronic medical conditions such as cardiovascular disease and diabetes mellitus. The comorbidity of major depressive and anxiety disorders is associated with barriers to treatment and worse psychiatric outcomes, including treatment resistance, increased risk for suicide, greater chance for recurrence, and greater utilization of medical resources. Effective recognition and treatment of anxiety and depression may be associated with functional improvement in the medical disorders (eg, lower HbA1c level in patients with diabetes). Paying careful attention to the development of anxiety and depression may also positively impact the economic burden of these disorders. To help primary care physicians better understand the comorbidity of depression and anxiety and medical disorders, the authors describe three case scenarios.