Depression and heart disease affect millions of people worldwide. Studies have shown that depression is a significant risk factor for new heart disease and that it increases morbidity and mortality in established heart disease. Many hypothesized and studied mechanisms have linked depression and heart disease, including serotonergic pathway and platelet dysfunction, inflammation, autonomic nervous system and hypothalamic-pituitary-adrenal axis imbalance, and psychosocial factors. Although the treatment of depression in cardiac patients has been shown to be safe and modestly efficacious, it has yet to translate into reduced cardiovascular morbidity and mortality. Understanding the impact and mechanisms behind the association of depression and heart disease may allow for the development of treatments aimed at altering the devastating consequences caused by these comorbid illnesses.