The treatment of coronary atherosclerosis requires an understanding of the pathophysiology of plaque rupture. The rupture of lipid-laden, macrophage-rich plaques initiates unstable angina, acute myocardial infarction and sudden cardiac death. Plaque rupture occurs when the circumferential tension on a plaque exceeds its tersile strength, an event that cannot be predicted by coronary angiography. The incidence of plaque rupture appears to be reduced in patients receiving cholesterol-lowering therapy, beta-adrenergic blocking agents and, possibly, angiotensin-converting enzyme inhibitors and antioxidants, Not all ruptured coronary plaques produce an acute coronary syndrome. The consequences of plaque rupture depend on the extent of thrombus formation over the fissured plaque. This is determined by flow characteristics within the vessel as well as the activity of the thrombotic and fibrinolytic systems. Recent advances in cardiovascular molecular biology, coronary diagnostic techniques and cardiac therapeutics have opened windows of opportunity to study and modify the factors leading to plaque rupture. The total modification of gene expression to alter plaque composition and to elucidate and subsequently inhibit the prothrombotic and fibrino lytic defects that promote coronary thrombosis may, in future, prevent plaque rupture and its consequences. The application of such a concerted interdisciplinary approach promises a paradigm shift in the management of coronary artery disease toward the prevention of plaque rupture and its sequelae.