Significance: The 3-hydroxy-methylglutaryl coenzyme A reductase inhibitors or statins are important therapeutic agents for lowering serum cholesterol levels. However, recent studies suggest that statins may exert atheroprotective effects beyond cholesterol lowering. These so-called “pleiotropic effects” include effects of statins on vascular and inflammatory cells. Thus, it is important to understand whether other signaling pathways that are involved in atherosclerosis could be targets of statins, and if so, whether individuals with “overactivity” of these pathways could benefit from statin therapy, regardless of serum cholesterol level. Recent Advances: Statins inhibit the synthesis of isoprenoids, which are important for the function of the Rho/Rho-associated coiled-coil containing kinase (ROCK) pathway. Indeed, recent studies suggest that inhibition of the Rho/ROCK pathway by statins could lead to improved endothelial function and decreased vascular inflammation and atherosclerosis. Thus, the Rho/ROCK pathway has emerged as an important target of statin therapy for reducing atherosclerosis and possibly cardiovascular disease. Critical Issues: Because atherosclerosis is both a lipid and an inflammatory disease, it is important to understand how inhibition of Rho/ROCK pathway could contribute to statins' antiatherosclerotic effects. Future Directions: The role of ROCKs (ROCK1 and ROCK2) in endothelial, smooth muscle, and inflammatory cells needs to be determined in the context of atherogenesis. This could lead to the development of specific ROCK1 or ROCK2 inhibitors, which could have greater therapeutic benefits with less toxicity. Also, clinical trials will need to be performed to determine whether inhibition of ROCKs, with and without statins, could lead to further reduction in atherosclerosis and cardiovascular disease. Antioxid. Redox Signal. 20, 1251–1267.