The manifestations of coronary artery disease are varied. They all arise as a consequence of the deposition of atherosclerotic plaque within the vessel wall. The most feared sequela of coronary artery disease is sudden and unexpected death in the ostensibly healthy patient. Plaque rupture of hemodynamically insignificant atherosclerotic plaques and ensuing thrombosis is likely responsible for a large proportion of such deaths. Identifying populations at increased risk for sudden death would represent a major advance. Such screening is contingent upon identification of DNA sequence variants that predispose individuals to plaque rupture. Phenotyping is not sufficiently nuanced to detect such variants on a large scale, so we are limited to end points that are crude surrogates for plaque rupture. As imaging modalities are refined and our ability to recruit large numbers of appropriate patients is facilitated by the formation of alliances, our ability to probe this conundrum via a genome-wide approach will improve.