Clinical trials have firmly established that 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors (statins) can induce regression of vascular atherosclerosis as well as reduction of cardiovascular-related morbidity and death in patients with and without coronary artery disease. These beneficial effects of statins are usually assumed to result from their ability to reduce cholesterol synthesis. However, because mevalonic acid is the precursor not only of cholesterol but also of many nonsteroidal isoprenoid compounds, inhibition of 3-hydroxy-3-methylglutaryl-coenzyme-A reductase may result in pleiotropic effects. Indeed, statins can interfere with major events involved in the formation and the evolution of atherosclerotic lesions, such as arterial myocyte migration and proliferation and cholesterol accumulation, independent of their hypolipidemic properties. The aim of this article is to focus on clinical and experimental data that show that statins possess effects beyond cholesterol lowering, particularly on arterial smooth muscle cell proliferation. The contribution of these direct vascular effects to the reduction of cardiovascular events observed in clinical trials with statins represents one of the major challenges for future studies to understand the antiatherosclerotic benefits of these agents.