Convincing evidence from basic research and animal studies shows that HMG CoA reductase inhibitors or statins, exert cardiovascular protective effects beyond cholesterol-lowering. Because of the central role of LDL-C in mediating vascular pathology and the efficacy of statins for lowering LDL-C, the clinical importance of these additional non-lipid effects remains to be determined. Nevertheless, there is growing evidence from recent clinical trials, which suggests that some of the beneficial effects of statins may be unrelated to changes in LDL-C. Indeed, in animal studies, many of the cholesterol-independent or “pleiotropic” effects of statins are due predominantly to inhibition of isoprenoid, but not cholesterol synthesis. Thus, with the recent findings of the HPS and ASCOT-LLA, the potential cholesterol-independent effects of statins have shifted the treatment strategy from numerical lipid parameters to the global assessment of cardiovascular risks.