Despite advances in the pharmacotherapy of atherosclerosis, the most successful agents used to treat this disease - statins - remain ineffective for the primary or secondary prevention of myocardial infarction in about two-thirds of patients. The lack of a more robust treatment effect underscores the limitations of lipid lowering alone and emphasizes the complexity of the disease and the need for targeting other critical processes. Further, despite the rapid progress in newer imaging modalities, the inability adequately to characterize lesions in individual patients beyond simple angiographic terms presents another problem. We need to be able to understand in living patients the histologic characteristics of non-flow limiting lesions and how these relate to risk for future events. Moreover, we also need to be able to modify critical elements within the atherosclerotic plaque, specifically macrophage foam cells, neoangiogenesis, necrotic core size, and fibrous cap thickness. These advancements will require newer pharmacologic agents and clinical refinements in the monitoring of treatment effects.