The lesion responsible for the overwhelming majority of acute coronary events is plaque disruption or erosion with superimposed thrombosis. The term "vulnerable plaque" has been used to describe those atherosclerotic plaques that are particularly susceptible to disruption. Vulnerable plaques are generally characterized as those having a thin inflamed fibrous cap over a very large lipid core. However, only a small percentage of such plaques rupture, and plaques with different characteristics may also rupture and thrombose. Most autopsy, intravascular ultrasound, and recent computed tomography angiographic studies of coronary arteries reveal large plaques at sites of rupture. While angiographic data are said to show less severe narrowing at sites of plaque rupture, actual review of data indicates that, even angiographically, more than 50% of plaques have greater than 75% cross-sectional area stenosis at sites of plaque rupture. If plaque rupture is more common at the shoulder region of a plaque, one could envision that this would be at a peripheral site of the plaque where the plaque may not be as large or occlusive. New knowledge about vulnerable plaques is emerging through the evolution of novel techniques used to study plaques in vivo. These methods combine sophisticated imaging techniques, often in conjunction with molecular biomarkers, that provide new insights into plaque biology. Since atherosclerotic coronary artery disease is such a widespread and fatal disease, it is important that we continue to strive for a greater understanding of the nature of the vulnerable plaque. Only then can rational interventions for this disorder be developed and implemented.