Over the past four decades, no class of drugs has had more impact on cardiovascular health than the HMC-CoA reductase inhibitors or statins. Developed as potent lipid-lowering agents, statins were shown to reduce mortality and morbidity of patients who are at risk for cardiovascular disease. However, retrospective analyses of some of these clinical trials have uncovered some aspects of their clinical benefits that may be additional to their lipid-lowering effects. In cell culture and animal studies, these effects alter the expression of endothelial nitric oxide synthase, the stability of atherosclerotic plaques, the production of pro-inflammatory cytokines and reactive oxygen species, the reactivity of platelets, and the development of cardiac hypertrophy and fibrosis. Such cholesterol-independent or "pleiotropic" effects of statins generated intense interest as to their potential mechanism and created debate over their relative contribution to cardiovascular risk reduction. One potential mechanism for statin pleiotropy is through inhibition of isoprenoid synthesis and protein prenylation. In particular, the prenylation of Rho GTPases such as Rho, Rac, and Cdc42 is critical to their cellular localization and function. Thus, inhibition of Rho and its downstream effector, Rho kinase, by statins may constitute an important pleiotropic mechanism that could be exploited therapeutically for non-lipid conditions beyond cardiovascular disease.