Several reports have demonstrated apoptosis in the advanced human atheroma. Most clinical events however, are precipitated by plaque rupture, to a lesser extent erosion, and the development of occlusive thrombi. Whether the extent of apoptosis can influence lesion stability is not precisely known, however, there is emerging data supporting this role. Obvious difficulties arise when studying apoptosis in atherosclerotic plaques because of the complex nature of the disease and lack of an experimental model of plaque instability. This article applies a systematic approach to discuss the issue of apoptosis in context of early disease to complex symptomatic lesions that may become fatal.