Cholesterol, an integral component of animal cell membranes, is the precursor for corticosteroid hormones and bile acids. Cholesterol ester and triglyceride, another insoluble (neutral) lipid, are transported with proteins termed apolipoproteins in particles called lipoproteins. Apolipoprotein E (apoE) is important in lipoprotein metabolism. It is produced in the liver, associates with large triglyceride-rich lipoproteins that are transformed to remnant lipoproteins with the loss of triglyceride by releasing fatty acids to adipose and muscle tissues, and mediates the uptake of the remnant lipoproteins in the liver as it is a ligand for several receptors. Three common apoE variants (apoE2, apoE3, and apoE4) result in small differences in lipoprotein metabolism detectable by conventional testing of plasma cholesterol and triglyceride. ApoE2, a poor ligand for clearance of remnant lipoproteins, paradoxically lowers plasma cholesterol and apoE4 raises it. Homozygosity of apoE2 may in some individuals cause a severe mixed hyperlipidemia with a high risk of atherosclerosis due to dysbetalipoproteinemia that is also seen with heterozygosity for some less common variants of apoE. Other variants of apoE may in addition cause kidney failure by deposition at the glomerulus. A rare variant of apoE can mimic familial hypercholesterolemia. ApoE4 not only raises the risk of vascular disease but also promotes dementia. The role of apoE is discussed in normal and deranged lipoprotein metabolism with an emphasis on dysbetalipoproteinemia. Insight in the importance of apoE in cholesterol metabolism promotes recognition of severe disorders as well as the variability of metabolism in the population at large.