Prospective epidemiologic data consistently show that elevated C-reactive protein (CRP) levels are associated with an increased risk of subsequent cardiovascular events in apparently healthy populations, and accumulating laboratory research is uncovering possible mechanisms by which CRP may influence the development of atherothrombotic disease. CRP is a stronger predictor of cardiovascular disease than is low-density lipoprotein (LDL) cholesterol. CRP adds prognostic information at all levels of the calculated Framingham risk score and at all levels of severity of the metabolic syndrome. Commercially available high-sensitivity assays suitable for use in clinical settings allow for the routine assessment of CRP as a useful adjunct in cardiovascular risk screening. When such assays are used, CRP levels of less than 1, 1 to 3, and greater than 3 mg/L differentiate patients at low, moderate, and high risk, respectively, for future cardiovascular events. Persons with high CRP but normal LDL cholesterol comprise a high-risk group frequently overlooked in clinical practice. Knowledge of their high-risk status may improve these patients’ compliance with recommended lifestyle changes that are likely to improve prognosis. Preliminary data suggest that individuals with elevated CRP but low LDL cholesterol may benefit from pharmacologic interventions, including statin therapy. Large-scale trials are underway to assess the net efficacy and public health impact of this approach to the primary prevention of myocardial infarction and stroke.