Elevated low-density lipoprotein cholesterol is an important risk factor for atherothrombotic arterial disease. HMG-CoA reductase inhibitors, or statins, are very effective in lowering cholesterol levels, and several trials using statins have shown reductions in mortality and cardiovascular events, leading to the recent recommendations that all patients with known vascular disease, or who are at high risk for vascular disease, should be considered candidates for statin therapy. Yet statins reduce cardiovascular events by only about 20%–40%. Nonstatin therapies (either as monotherapy or in addition to statins) to reduce LDL cholesterol by mechanisms that do not involve inhibition of HMG-CoA reductase are likely to be useful for patients in need of LDL reduction; particularly those who either cannot take statins or respond only partially or not at all to statins alone. These therapies include cholesterol absorption inhibitors, Acyl-CoA cholesterol acyl transferase inhibitors, farnesoid X receptor antagonists, sterol-regulating binding protein cleavage activating protein, and microsomal triglyceride transfer protein.