Current US lipid-lowering guidelines indicate that optimal plasma levels of low-density lipoprotein cholesterol (LDL-C) are <100 mg/dL, and targeting global risk assessment has significantly increased the number of individuals who are candidates for intensive plasma lipid-lowering therapy. There is accumulating evidence that reduction of plasma LDL-C concentrations to targets even lower than those currently recommended may provide additional benefit in coronary heart disease (CHD) prevention. For example, the Heart Protection Study (HPS) found that statin treatment initiated at a baseline LDL-C plasma level of <100 mg/dL in patients at high risk provided a relative benefit in reducing the incidence of cardiovascular events that was similar to when it was initiated at higher LDL-C plasma levels. In addition, it is becoming clear that CHD risk, and the need for intensive lipid-lowering treatment, may be underestimated in some populations, including individuals with the metabolic syndrome. In the overall primary prevention population, high-sensitivity C-reactive protein measurement has been shown to identify individuals at high risk of cardiovascular events who would not be considered at high risk on the basis of current systems of risk assessment. The increasing focus on intensive plasma lipid lowering to reduce CHD risk has placed a premium on the development of therapies with improved ability to reduce plasma levels of LDL-C.