Depression frequently is comorbid with a variety of medical illnesses; individuals who have such comorbidities may have increased morbidity and lower functional status. Usual antidepressant treatments can be effective in depressed patients who have comorbid medical illness. These patients, however, experience lower rates of recovery and remission of depressive symptoms and higher rates of relapse during follow-up than seen in patients who have MDD with no medical comorbidity. Comorbid medical illness therefore is a marker of treatment resistance in MDD. Collaborative treatments combining antidepressants, psychotherapy, education, and case management may be effective and could overcome the risk of treatment resistance. Two clinical strategies seem warranted in light of the studies presented here: (1) an increased index of suspicion for depression in medically ill patients, and (2) more intensive antidepressant treatment in depressed patients who have medical comorbidity.