Because the consequences of ischemic vascular disease are projected to be the leading cause of morbidity in the next century, it is critical to continue to develop preventive strategies and therapies for unstable vascular syndromes. A great deal has been learned about the natural history of atherosclerosis in the past decade, and it is now widely accepted that unstable atheroma and subsequent plaque rupture is a leading cause of acute myocardial infarction. However, recent studies indicate that plaque rupture may be a common and important cause of many cardiovascular diseases in addition to acute myocardial infarction. Available data indicate that lipid-rich pools and thin fibrous caps combine to establish high mechanical stresses in the lesion. In addition, active extra-cellular matrix degradation at these locations causes the fibrous cap to rupture at these locations. The pathophysiology of plaque rupture causing myocardial infarction is reviewed. Also, recent exciting data that suggest that prevention of plaque rupture may have dramatic and unforeseen clinical benefits are discussed.