The most important action of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) is their ability to lower levels of low-density lipoprotein (LDL) cholesterol. Statins have proved highly effective in reducing the risk of cardiovascular events in both primary and secondary prevention studies. However, the magnitude of risk reduction associated with statins is greater than that predicted on the basis of LDL cholesterol lowering alone. A likely explanation for this effect is the anti-inflammatory action of statins. Following the observation that high-sensitivity C-reactive protein (hs-CRP) is a powerful predictor of cardiovascular events, investigators in the Cholesterol and Recurrent Events (CARE) and Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) trials demonstrated that the magnitude of risk reduction associated with statin therapy was higher among those with elevated hs-CRP levels. In addition, there is accumulating evidence that statins lower plasma levels of hs-CRP in a manner largely independent of LDL cholesterol lowering. In contrast, little benefit has been demonstrated for statin therapy in the absence of both hyperlipidemia and inflammation. Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) is a large multinational, long-term, double-blind, placebo-controlled, randomized clinical trial designed to assess directly whether statin therapy (rosuvastatin 20 mg/day) should be given to apparently healthy individuals with low LDL cholesterol levels but elevated hs-CRP levels--a critical issue for the prevention of cardiovascular disease. Support for the concept behind the JUPITER trial is also now available from several recent trials comparing different intensities of statin therapy on disease progression as well as clinical end points. These studies indicate that the hs-CRP level achieved after initiation of statin therapy may be as important as the LDL cholesterol level achieved. All of these data raise the possibility that hs-CRP could be used to target high-risk patients who may benefit from early statin use. Ongoing work will determine whether hs-CRP reduction, independent of LDL cholesterol reduction, results in a net clinical benefit.