Plasma levels of high-density lipoprotein (HDL) cholesterol and its major protein, apolipoprotein A-I, are inversely correlated with the incidence of atherosclerotic cardiovascular disease. Low HDL cholesterol and apolipoprotein A-I levels often are found in association with other cardiovascular risk factors, including the metabolic syndrome, insulin resistance, and type 2 diabetes mellitus. However, overexpression of apolipoprotein A-I in animals has been shown to reduce progression and even induce regression of atherosclerosis, indicating that apolipoprotein A-I is directly protective against atherosclerosis. A major mechanism by which apolipoprotein A-I inhibits atherosclerosis may be by promoting cholesterol efflux from macrophages and returning it to the liver for excretion, a process termed reverse cholesterol transport. This article focuses on new developments in the regulation of reverse cholesterol transport and the clinical implications of those developments.