Atherosclerosis is a chronic inflammatory disease of large- and medium-sized arteries characterized by the buildup of lipid-containing plaques within arterial walls. It is manifested as coronary artery disease, ischemic stroke, and peripheral arterial disease. Dyslipidemia, featured by elevations in plasma levels of low-density lipoprotein (LDL) and triglyceride and reductions in high-density lipoprotein (HDL), is causally associated with risk of atherosclerosis. Apolipoprotein E (APOE) plays a key role in the clearance of lipoproteins in the liver by acting as a ligand for cell membrane receptors. Common variants in APOE gene are associated with inter-individual variation in plasma cholesterol and triglyceride levels and susceptibility to atherosclerosis. Rare APOE gene variants contribute to monogenic and polygenic dyslipidemia and premature atherosclerosis. Apoe deficiency causes spontaneous hypercholesterolemia and atherosclerosis in mice. Circulatory APOE is produced primarily by the liver and also by adipocytes, monocytes/macrophages, vascular smooth muscle cells, and other cell types. Beyond its role in lipoprotein metabolism, APOE suppresses atherosclerosis by protecting against endothelial dysfunction, LDL oxidation, inflammation, foam cell formation, and vascular smooth muscle cell proliferation and migration. Thus, APOE can be a valuable target for developing anti-atherosclerotic therapies.