The population impact of sudden death remains an unresolved problem despite growing insights into pathophysiologic mechanisms and therapeutic approaches. To make further progress, basic scientists, clinical investigators, and epidemiologists must merge their efforts to achieve better predictive strategies. Better understanding of basic physiologic mechanisms and integration of multiple points of attack in the cascade of coronary atherosclerosis are required. Identification of genetic markers of risk at all levels of the cascade offer one avenue for improving risk predictions. The epidemiologic strategies must go beyond multivariate analysis to the level complex systems analysis of the multiple components of the cascade. Targets for such approaches are discussed.