The relationship between depression and cardiovascular disease is complex and multifaceted. There is a growing body of evidence that depression significantly and adversely affects cardiovascular health. Perhaps the most prominent finding is the documented increase in mortality rate in patients with depression after myocardial infarction. The critical questions of interest to both the clinician and researcher are whether there are safe and effective treatments for depression in patients with heart disease and whether treatment of depression reduces the increased risk of cardiac morbidity and mortality. Although the data are limited and are primarily from open or comparator trials, the tricyclics (TCAs) and selective serotonin reuptake inhibitors (SSRI) are effective for treatment of depression in patients with ischemic heart disease (IHD), and response rates are comparable with those reported in depressed patients without heart disease. In terms of safety, the TCAs are associated with documented adverse cardiovascular effects, including increases in heart rate, orthostatic hypotension, and conduction delays. Use of TCAs in patients with IHD carries a proven increased risk of cardiac morbidity and perhaps of mortality as well. The SSRI appear to be relatively safe and effective in the treatment for depression in patients with comorbid IHD.