The failure of high-density lipoprotein (HDL)-raising agents to reduce cardiovascular disease (CVD) together with recent findings of increased cardiovascular mortality in subjects with extremely high HDL-cholesterol levels provide new opportunities to revisit our view of HDL. The concept of HDL function developed to explain these contradictory findings has recently been expanded by a role played by HDL in the lipolysis of triglyceride-rich lipoproteins (TGRLs) by lipoprotein lipase. According to the reverse remnant-cholesterol transport (RRT) hypothesis, HDL critically contributes to TGRL lipolysis via acquirement of surface lipids, including free cholesterol, released from TGRL. Ensuing cholesterol transport to the liver with excretion into the bile may reduce cholesterol influx in the arterial wall by accelerating removal from circulation of atherogenic, cholesterol-rich TGRL remnants. Such novel function of HDL opens wide therapeutic applications to reduce CVD in statin-treated patients, which primarily involve activation of cholesterol flux upon lipolysis.