Coronary artery disease (CAD) as well as depression are both highly prevalent diseases. Both cause a significant decrease in quality of life for the patient and impose a significant economic burden on society. There are several factors that seem to link depression with the development of CAD and with a worse outcome in patients with established CAD: worse adherence to prescribed medication and life style modifications in depressive patients, as well as higher rates in abnormal platelet function, endothelial dysfunction and lowered heart rate variability. The evidence is growing that depression per se is an independent risk factor for cardiac events in a patient population without known CAD and also in patients with established diagnosis of CAD, particularly after myocardial infarction. Treatment of depression has been shown to improve patients' quality of life. However, it did not improve cardiovascular prognosis in depressed patients even though there is open discussion about the trend to better outcome in treated patients. Large scale clinical trials are needed to answer this question. Selective serotonin reuptake inhibitors seem to be preferable to tricyclic antidepressants for treatment of depressive patients with comorbid CAD because of their good tolerability and absence of significant cardiovascular side effects. Hypericum perforatum (St. John's wort), an increasingly used herbal antidepressant drug should be used with caution due to severe and possibly dangerous interaction with cardioactive drugs.