Atherosclerotic cardiovascular disease remains the leading cause of death in the industrialized world. Most cardiovascular deaths result from acute coronary syndromes, including unstable angina pectoris and acute myocardial infarction. Coronary syndromes often arise from acute coronary thrombosis, itself commonly a result of disruption or rupture of the fibrous cap of a lipid-laden atherosclerotic plaque. Despite this huge clinical burden of atherosclerotic plaque instability, our understanding of the molecular mechanisms mediating atherosclerotic plaque disruption and rupture, at a cellular level, remains limited. Placed in a clinical context, this review discusses our current understanding of the molecular basis for atherosclerotic plaque instability, with particular emphasis on the process of apoptosis-or programmed cell death-seen increasingly as playing a key role in a number of cell types within the vessel wall.