The association between cardiovascular disease and mental depression is multifaceted and likely bidirectional. Depressed patients are at significantly higher risk for cardiac morbidity and mortality even in the absence of a diagnosis of major depression, whereas mental depression is nearly 3 times more frequent in patients after an acute myocardial infarction and contributes to a worse prognosis. Therefore, depressed patients might become trapped in a harmful loop, where mental symptoms might be worsened by the synergistic effects of stress and cardiovascular risk factors, and where they are otherwise vulnerable to acute cardiovascular events due to the synergistic effects of mental stress and an underlying atherothrombotic disorder. Although the exact pathway(s) underlying the interplay between depression and cardiovascular disease remains to be elucidated, the mechanisms most often implicated include hormonal variations, metabolic abnormalities, hypercoagulability, increased platelet aggregation, inflammation, and endothelial dysfunction. This article aims to review the biological and clinical links between depression and cardiovascular disease.