High-density lipoproteins (HDLs) are strongly related to risk of atherosclerotic cardiovascular disease. Low levels of HDL cholesterol are a major cardiovascular risk factor, and overexpression of the major HDL protein, apolipoprotein (apo) A-I, markedly inhibits progression and even induces regression of atherosclerosis in animal models. Clinical data regarding the effect of increasing HDL cholesterol on vascular events are limited. HDL remains an important potential target for therapeutic intervention. A variety of gene products are involved in the regulation of HDL metabolism. Yet, the mechanisms by which HDL inhibits atherosclerosis are not yet fully understood. There remains much to be learned about HDL metabolism and its relation to atherosclerosis and other cardiovascular risk factors.