OBJECTIVE: The present paper reviews the evidence that depression is a risk factor for the development and progression of coronary artery disease (CAD). METHODS: MEDLINE searches and reviews of bibliographies were used to identify relevant articles. Articles were clustered by theme: depression as a risk factor, biobehavioral mechanisms, and treatment outcome studies. RESULTS: Depression confers a relative risk between 1.5 and 2.0 for the onset of CAD in healthy individuals, whereas depression in patients with existing CAD confers a relative risk between 1.5 and 2.5 for cardiac morbidity and mortality. A number of plausible biobehavioral mechanisms linking depression and CAD have been identified, including treatment adherence, lifestyle factors, traditional risk factors, alterations in autonomic nervous system (ANS) and hypothalamic pituitary adrenal (HPA) axis functioning, platelet activation, and inflammation. CONCLUSION: There is substantial evidence for a relationship between depression and adverse clinical outcomes. However, despite the availability of effective therapies for depression, there is a paucity of data to support the efficacy of these interventions to improve clinical outcomes for depressed CAD patients. Randomized clinical trials are needed to further evaluate the value of treating depression in CAD patients to improve survival and reduce morbidity.