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In the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines, the emphasis of lipid-lowering therapy is placed on reaching target plasma low-density lipoprotein cholesterol (LDL-C) levels in order to reduce the risk for coronary heart disease (CHD). Although therapeutic lifestyle changes can have a positive effect on LDL-C levels, the ATP III recognizes that a majority of patients with dyslipidemia will also require drug therapy to achieve lipid targets. Currently, only a small percentage of patients, including those with CHD, are reaching goal. Early aggressive use of the effective lipid-lowering agents currently available is critical to achieve target lipid levels in a greater number of patients. Use of drug combinations further enhances the likelihood of achieving target lipid levels. Ideally, the combination of therapeutic modalities used both the endogenous and exogenous pathways of cholesterol synthesis to reduce the amount produced in the body, as well as the amount absorbed from the diet. This article reviews the pharmacotherapeutic effects of combination therapy, summarizes the strengths and weaknesses of current lipid-lowering drug combinations, and identifies the potential impact of the novel cholesterol absorption inhibitor ezetimibe on the LDL-C treatment algorithm.