Atherosclerotic cardiovascular disease is the major killer in industrialized societies. Treatment of this disorder via LDL lowering, particularly with statin drugs, has been partially effective but no panacea. Many patients developing coronary heart disease (CHD) do not have markedly elevated LDL but rather have low HDL levels, alone or accompanied by hypertriglyceridemia. The strong inverse relationship between HDL levels and atherosclerotic cardiovascular disease has been known for more than 25 years (1), but, surprisingly, no effective therapy specifically directed at HDL has yet been developed. This reflects uncertainty about the mechanisms underlying the protective effect of HDL, and also a lack of attainable therapeutic targets. The oldest theory to explain HDL’s protective relationship is the reverse cholesterol transport (RCT) hypothesis, which holds that HDL mediates the movement of cholesterol from peripheral cells, including macrophage-derived foam cells in the arterial wall, back to the liver, where it is excreted into bile (2)(Figure 1). The RCT theory evolved from an understanding of the role of HDL in transporting cholesterol through the bloodstream to the liver and the finding that HDL and its major apolipoprotein, apoA-I, could remove cholesterol from foam cells (3, 4). A number of other properties of HDL could also be involved in its protective effect. Thus, HDL can suppress expression of cytokine-induced endothelial cell adhesion molecules and block the migration of macrophages into the subendothelial space of blood vessels. HDL protects LDL from oxidation by a variety of mechanisms and may serve as an anticoagulant and antiplatelet agent (see ref. 5). To what extent the various properties of HDL influence the progression of cardiovascular disease remains uncertain. Evidence for a direct protective effect of HDL in atherosclerosis came with the development of transgenic mice overexpressing the major HDL apoprotein, apoA-I. Transgenic mice expressing human apoA-I have increased HDL levels and are substantially protected from developing atherosclerosis, induced either by diet or genetic manipulation (5). Furthermore, serum from apoA-I transgenic rats stimulates cellular cholesterol efflux to a greater extent than normal serum (6), and apoA-I transgenic mice have increased transport of cholesterol to the liver (7); apoA-I knockout mice, conversely, have decreased flux (8). Placing the apoA-I transgene in the background of the otherwise proatherogenic apoE deletion genotype yields mice that are protected from atherosclerosis, even though they show no alteration of endothelial adhesion molecule (VCAM-1, ICAM-1) expression in lesions or of oxidationassociated epitopes in plasma (9). While not conclusive, these findings are consistent with increased RCT as the protective mechanism in these animals.