Results from large-scale clinical trials of lipid lowering with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have led to a revolution in the management of atherosclerosis. In addition to their potent effect on serum lipid levels, statins influence several other cellular pathways, including those involving inflammatory, oxidative, and thrombotic processes. These effects clearly have the potential to beneficially modify the atherogenic process, and it has been suggested that they contribute to the impressive results seen in the clinical trials. We review the clinical evidence for benefits of statin therapy that are distinct from their effect on lipid biology. In particular, we address three key issues: the role of statins in diseases not traditionally associated with elevated cholesterol levels; whether clinical benefits are seen with statin therapy before an effect on lipid levels; and whether the magnitude of clinical benefit observed with statin therapy is unrelated to the degree of cholesterol reduction. At present, low-density-lipoprotein lowering seems to be the primary mechanism underlying the clinical benefits of statin therapy and should remain the focus of risk-reduction strategies in clinical practice.