Depression is a common comorbid condition in patients with coronary artery disease and a well-documented risk factor for recurrent cardiac events and mortality. The exact mechanisms underlying the interplay between depression and ischemic heart disease remain poorly understood and the same is true for the most effective depression treatment for cardiac patients. This review summarizes current knowledge regarding the prognostic role of depression in patients with coronary artery disease, the pathophysiologic pathways involved, and the effects of antidepressant therapy on cardiovascular disease outcomes. With recent evidence suggesting that selective serotonin reuptake inhibitors may improve survival after myocardial infarction in patients with depression, diagnosis and treatment of this co-morbidity may be essential for the clinical management of coronary artery disease.