Depression and coronary heart disease are common conditions that often occur together. Evidence shows that the co-occurrence of these illnesses is not random but driven by depression as a risk factor for the occurrence and progression of coronary heart disease. This link is due, in part, to the impact that depression has on neuroendocrine pathways leading to increased platelet activation, cortisol and catecholamine excess, and altered autonomic nervous system function that influence the pathogenesis and progression of coronary atherosclerosis and subsequent heart disease. We know that treating depression in patients with coronary heart disease improves the symptoms and signs of depression. Evidence is less compelling that treating depression improves the morbidity and mortality of coronary heart disease. However, early findings suggest that some antidepressants may improve the course of coronary heart disease and improve patient compliance with various cardiac interventions. We outline a practical approach to the treatment of depression in patients with coronary heart disease. This approach includes education, counseling, antidepressant drugs, and referral when appropriate.