The most common cause of acute coronary syndrome (ACS) is rupture of an atherosclerotic lesion containing a large necrotic core and a thin fibrous cap followed by acute luminal thrombosis because the rupture of the thin fibrous cap allows contact of the platelets with the highly thrombogenic necrotic core. Pathologic studies have suggested that the precursor of the ruptured plaque is the so-called thin cap fibroatheroma (TCFA). Unfortunately, true natural history studies of TCFAs and their transition to ruptured plaques are rare. Most of the data and concepts have been inferred from studies performed at a single point in time. Intravascular ultrasound (IVUS) studies have shown ruptured plaques in approximately two thirds of ACS culprit lesions and occur in predictable locations. The features that differentiate secondary, nonculprit plaque ruptures from those that cause ACS events appear to be superimposed thrombosis and lumen compromise, either from the thrombus or from the underlying lesion. Secondary plaque ruptures appear to heal with optimal medical therapy. In vivo definitions of TCFAs have been derived from pathology study to include positive remodeling, a fibrous cap less than 100 microm (and perhaps <65 microm) at its minimum thickness, macrophage infiltration especially in the thin fibrous cap, a large lipid/necrotic core often containing hemorrhage and/or speckled or diffuse calcification (not enough to increase plaque stability although the absence of any calcium is also rare in rupture-prone plaques), and abundant intraplaque vasa vasorum and/or hemorrhage. Early data from in vivo imaging have substantiated the pathologic observations, but have also suggested that spontaneous stabilization of TCFAs with medical therapy alone is possible.