Recent research on the effects of behavioral activities on myocardial ischemia in coronary artery disease patients has provided a pathophysiologic model for understanding the mechanisms by which mental stress can trigger clinical cardiovascular events. This article reviews epidemiologic research implicating psychosocial stress as an acute trigger of myocardial infarction in patients with pre-existing coronary artery disease, and evidence for the pathophysiologic effects of acute mental stress in individuals with pre-existing coronary artery disease. Via its actions on the central and autonomic nervous systems, stress can produce a cascade of physiologic responses in vulnerable individuals that may lead to myocardial ischemia, ventricular fibrillation, plaque rupture, or coronary thrombosis. Also reviewed are field and laboratory studies that suggest important causal links between mental stress and myocardial ischemia, and evidence suggesting clinical significance for vulnerability to mental stress-induced ischemia.