A non-optimal plasma concentration of lipids is among the major modifiable risk factors of atherosclerosis. Therefore, the prevention of cardiovascular disease by means of lipid-lowering therapy with statins and other agents is of great importance for patient groups where a lifestyle change, for example, diet modification, does not lead to adequately reduced lipid levels. The response of low-density-lipoprotein cholesterol (LDL-C) levels to statin therapy is highly variable. This is partly attributed to hereditary variation in genes involved in pharmacokinetics, pharmacodynamics and lipid metabolism. The pharmacogenetics of lipid-lowering therapy have been investigated for more than 40 different genes. The gene for apolipoprotein E (APOE) has been the most frequently studied, particularly regarding the epsilon2/epsilon3/epsilon4 polymorphism. Those with the epsilon4 allele seem to have the poorest and those with the epsilon2 allele the strongest response to statins with regards to LDL-C levels. In addition, the epsilon2 carriers may reach the LDL-C treatment goals more frequently than epsilon4 carriers. Few studies have investigated the interaction of the APOE epsilon2/epsilon3/epsilon4 polymorphism and lipid-lowering therapy in relation to the course of coronary heart disease; the results are contradictory and so far inconclusive. This review summarizes the pharmacogenetic findings related to the influence of APOE gene variation on lipid responses and the prevention of coronary heart disease during lipid-lowering therapy.