Hypercholesterolemia is considered the primary risk factor for cardiovascular disease. An estimated 200 million prescriptions are issued per year for statins to treat hypercholesterolemia. Importantly, statins have additional beneficial effects independent of their effects on lipids. Recent studies have shown that statins reduce thrombosis via multiple pathways, including inhibiting platelet activation and reducing the pathologic expression of the procoagulant protein tissue factor. Many of the antithrombotic effects of statins are attributed to inhibiting prenylation of RhoA and effects on other intracellular signaling molecules such as NF-κB and KLF2. These antithrombotic activities of statins likely contribute to the ability of statins to reduce the incidence of cardiovascular death.