The recognition that plaque rupture is a key event in coronary thrombosis and that plaques that rupture tend to be subcritical stenoses associated with lipid-laden lesions has shifted the focus of etiologic research to factors leading to formation and rupture of unstable plaque, such as inflammation and impaired endothelial function. Inflammatory and infectious factors have long been known to be associated with CVD in epidemiologic studies and recognition of the importance of plaque rupture provides a plausible mechanism for this relationship. Continued research on inflammation and CVD risk in populations thus provides a promising avenue for elucidating mechanisms of plaque rupture. It also exemplifies the cyclical and complementary nature of risk factor identification in population and experimental studies, progressing from clinical events at the population level to the tissue and cellular level experimentally, and back to the tissue and population level in studies of subclinical disease.