Atherosclerosis is a slowly progressive degenerative disease occasionally characterized by a sudden shift in its natural history with a rupture of the atherosclerotic plaque and consequent acute thrombosis and clinical events. In recent years, biological and morphological factors responsible for the instability of coronary plaques have been identified. According to the most frequent pathophysiological sequence the fibrous cap that separates the lipid core of the atherosclerotic plaque from the circulation, ruptures thus exposing the highly thrombogenic biochemical elements and resulting in acute thrombosis and possible vessel occlusion. In this scenario, plaque morphology plays a crucial role along with systemic responses, such as activation of inflammation and coagulation cascade, in the definition of the patients at risk of acute myocardial infarction. Recent advances in intracoronary imaging techniques capable of defining the morphological characteristics of vulnerable plaques with high resolution, have given us the reasonable expectation that, in the immediate future, critical information on the pathophysiology of atherosclerosis and the direct causes of myocardial infarction can be obtained. It is conceivable that in the next few years these new high-resolution imaging techniques will be able to identify the crucial characteristics that define a vulnerable plaque that is likely to rupture. A scoring system designed to assess the specific risk of instability for any given atherosclerotic plaque could be generated with the purpose of identifying prospectively acute coronary events. In this perspective, optical coherence tomography is certainly the most promising imaging technique. Thus, the association of specific morphological information with systemic markers of vulnerability may allow in the near future to predict the true risk of acute myocardial infarction for each individual patient.