Major advances have been made in our understanding of the role of apolipoprotein E (apoE) in the onset and development of atherosclerosis. Increasing evidence from both animal and human studies suggests that apoE is able to protect against atherosclerosis by: a) promoting efficient uptake of triglyceride-rich lipoproteins from the circulation; b) maintaining normal macrophage lipid homeostasis; c) playing a role in cellular cholesterol efflux and reverse cholesterol transport; d) acting as an antioxidant; e) inhibiting platelet aggregation; and f) modulating immune function. In humans, apoE is polymorphic, and this genetic variation has a strong effect on its antiatherogenic characteristics. Thus, compared to the epsilon3 allele, the epsilon4 allele promotes atherosclerosis, whereas the epsilon2 allele is either pro- or anti-atherogenic, depending on the influence of both environmental and genetic factors. ApoE and its gene are prime targets for therapeutic intervention aimed at preventing or treating atherosclerotic vascular disease.