Major depression affects about one in five patients in the weeks after an acute myocardial infarction and is associated with an increased risk of cardiac morbidity and mortality. Consequently, there is considerable interest in the question of whether treating depression will improve medical prognosis in these patients. Safe, effective treatments for depression are available, but unless they also improve the underlying pathophysiological or behavioral mechanisms that contribute to cardiac morbidity and mortality, they may not have beneficial effects on prognosis. Altered cardiac autonomic tone is one of the leading candidate mechanisms. Unfortunately, a review of the available research reveals that cardiac autonomic tone often fails to normalize in patients treated for depression, and the research suggests that currently available treatments for depression will not necessarily improve cardiac event–free survival in patients who have had an acute myocardial infarction. Until there is convincing evidence that treatment can reduce the risk of cardiac morbidity and mortality, the principal reason to treat depression should continue to be to improve the quality of life of the patient who has had an acute myocardial infarction.