Apolipoprotein E is a multifunctional protein that is synthesized by the liver and several peripheral tissues and cell types, including macrophages. The protein is involved in the efficient hepatic uptake of lipoprotein particles, stimulation of cholesterol efflux from macrophage foam cells in the atherosclerotic lesion, and the regulation of immune and inflammatory responses. Apolipoprotein E deficiency in mice leads to the development of atherosclerosis and re-expression of the protein reduces the extent of the disease. This review presents evidence for the potent anti-atherogenic action of apolipoprotein E and describes our current understanding of its multiple functions and regulation by factors implicated in the pathogenesis of cardiovascular disease