This manuscript reviews the evidence that depression is associated with increased risk of mortality and explores the evidence that treating depression reduces that risk. The thought that depression and death are linked is ancient, but scientifically it has been difficult to prove. After the World War II, type "A" personality appeared capable of identifying cardiac patients at increased risk of death. By the mid 1970s that evidence appeared to weaken and may have been altered by the changing treatment of cardiovascular disease. At the same time, research began to focus on a diagnosis of depression as a predictor but it was 25 years before the association was firmly established. Originally examined in medically healthy in-dividuals followed for long periods of time, in the early 1990s epidemiological research began examining the influence of depression in patients with overt cardiovascular disease. That focus has been primarily on post-MI depression and the obvious question was if treating depression would reduce the risk. Such studies require a very large sample and initially there was no safety data available with any antidepressant drug. Gradually evidence has accumulated that SSRI antidepressants were safe and effective and there is a suggestion that they reduce not only depression but medical adverse events as well. However, that evidence is not definitive and the reason behind the association between depression and cardiovascular morbidity and mortality remains uncertain.