Major depressive disorder is a risk factor for the development of incident coronary heart disease events in healthy patients and for adverse cardiovascular outcomes in patients with established heart disease. Depression is present in 1 of 5 outpatients with coronary heart disease and in 1 of 3 outpatients with congestive heart failure, yet the majority of cases are not recognized or appropriately treated. It is not known whether treating depression improves cardiovascular outcomes, but antidepressant treatment with selective serotonin reuptake inhibitors is generally safe, alleviates depression, and improves quality of life. This article evaluates the importance of major depression in patients with cardiovascular disease, and provides practical guidance for identifying and treating this disorder.