Coronary artery disease (CAD) is the leading cause of morbidity and mortality in the United States, and a high concentration of low-density lipoprotein cholesterol (LDL-C) is a major risk factor for CAD. Current guidelines recommend the use of statins to lower LDL-C levels for the primary prevention of CAD based on an individual's risk factor profile and baseline LDL-C level. For moderaterisk individuals, those with 2 or more major risk factors for CAD and a Framingham risk score of 10% to 20%, the recommendation is to use a statin to lower LDL-C levels to less than 130 mg/dL. However, up to 40% of individuals who develop CAD have LDL-C levels lower than this cutoff. In 2004, the National Cholesterol Education Program Adult Treatment Panel III guidelines were updated to include an LDL-C goal of less than 100 mg/dL for individuals at moderately high risk of developing CAD. The guidelines identified several risk factors that when present would favor the use of pharmacological therapy to achieve this more aggressive LDL-C goal. This review evaluates the evidence supporting an LDL-C target of less than 100 mg/dL for moderately high-risk individuals and reviews those risk factors that when present help identify patients who would benefit from achieving this lower LDL-C goal. English-language publications in MEDLINE and references from relevant articles published between January 1, 1980, and November 30, 2008, were reviewed. Main keywords searched were coronary artery disease, hyperlipidemia, statins, cardiac risk factors, inflammatory markers, metabolic syndrome, and coronary artery calcium.