Clinical trials have firmly established that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) can induce the regression of vascular atherosclerosis and reduce cardiovascular-related morbidity and death in patients with and without coronary artery disease. It is usually assumed that these beneficial effects are due to the ability of statins to reduce cholesterol synthesis. However, because mevalonic acid is not only the precursor of cholesterol but also of many non-steroidal isoprenoid compounds, the inhibition of HMG-CoA reductase may lead to pleiotropic effects. As shown by the data reported in this review, some statins can interfere with major events involved in the formation of atherosclerotic lesions, regardless of their hypolipidemic properties. The relevance of these effects in humans remains to be established (particularly in view of the high statin doses required to produce a direct vascular action), thus their contribution to the reduction in cardiovascular events observed in clinical trials has become one of the major challenges for future studies aimed at clarifying the anti-atherosclerotic benefits of statins.