Although an early invasive strategy (angiography and percutaneous coronary intervention) is the convention in acute coronary syndrome (ACS)/non-ST-segment elevation myocardial infarction (MI) in the U.S., a conservative pharmacologic approach is common in other countries. Trial evidence has demonstrated a modest benefit with an angiographically guided approach; but patients having negative troponin values or who were receiving aspirin showed little or no benefit, and those without ST-segment changes had slightly worse outcomes. Limitations of angiography are clinically important. Identification of hemodynamically significant stenoses may be confounded by coronary remodeling. Also, most plaques, particularly those responsible for acute events, are extraluminal. Assessment of the luminal diameter of a lesion, which requires comparison with a normal reference segment, may be impossible because of the diffuse nature of the disease. Percutaneous coronary intervention after plaque rupture may itself cause embolization and no-reflow phenomena, leading to severe complications. In addition, most ruptures may be clinically silent. Evidence of a systemic inflammatory component suggests that ACS patients are at risk for plaque rupture at multiple sites. The inability of angiography to depict the true extent of atherosclerosis is supported by necropsy and transplant donor studies. A metabolic approach to this systemic disease is the only strategy designed to influence the behavior of both the small number of angiographically visible lesions and the large number of occult plaques. Statins and other agents decrease the incidence of death and MI by stabilizing atherosclerotic plaques throughout the coronary bed, reducing inflammation, collagen degradation, tissue factor expression, and vasomotor tone.