Acute myocardial infarction (AMI) and sudden cardiac death (SCD) are among the most serious and catastrophic of acute cardiac disorders, accounting for hundreds of thousands of deaths each year worldwide. Although the incidence of AMI has been decreasing in the US according to the American Heart Association, heart disease is still the leading cause of mortality in adults. In most cases of AMI and in a majority of cases of SCD, the underlying pathology is acute intraluminal coronary thrombus formation within an epicardial coronary artery leading to total or near-total acute coronary occlusion. This article summarizes our current understanding of the pathophysiology of these acute coronary syndromes and briefly discusses new approaches currently being researched in an attempt to define and ultimately reduce their incidence.