The world-wide importance of acute vascular syndromes is increasing. Acute events are usually triggered by fibrous cap disruption and subsequent thrombus formation. Histological studies have established specific structural features common among unstable plaques. The eccentric, lipid-laden plaque has to bear remarkably high mechanical stresses at the "shoulder regions". These internal stresses can reach thousands of millimeters of mercury. In addition, weakening of the extracellular matrix at these sites leads to fibrous cap rupture. Dynamic interactions between inflammatory mediators and matrix cause weakening of the plaque at these high stress locations, and it is likely that lowering cholesterol reduces both mechanical stresses and the inflammation that promotes fibrous cap weakening. Understanding the interplay of plaque architecture, mechanical properties, and matrix biology is critical in the future development of therapies to stabilize lesions.