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One of the major mechanisms whereby HDL particles are felt to protect against atherosclerosis is that of reverse cholesterol transport from atherosclerotic lesion macrophages to the liver, with subsequent excretion of cholesterol in the bile. This review focuses on recent progress in our understanding of reverse cholesterol transport and the factors that determine plasma HDL cholesterol concentrations.The liver and intestine are the major sites of apolipoprotein A-I synthesis and nascent HDL particle secretion. The liver has recently been shown to be a major contributor to the plasma HDL-cholesterol concentration, but the precise site or mechanism whereby hepatically-synthesized HDL acquire the bulk of their lipid content remains to be determined. Contrastingly, macrophages contribute little to the plasma HDL cholesterol pool, whereas the quantitatively small macrophage-specific reverse cholesterol transport contributes disproportionately to protection against atherosclerosis. Studies have highlighted the coordinate action of cell surface lipid transporters, cholesterol esterification enzymes and lipid transfer factors in the early steps of reverse cholesterol transport and the recycling of pre-β HDL particles to create a ready supply of cholesterol acceptor HDL particles. Most of the variation in plasma HDL-cholesterol levels in human populations is accounted for by variations in HDL clearance rather than production.Our understanding of the in-vivo metabolism of HDL particles and their role in reverse cholesterol transport is rapidly evolving, with long-standing concepts being constantly challenged by emerging evidence. An in-depth understanding of HDL metabolism will guide the rational design of novel pharmacological therapies that effectively protect against atherosclerosis.