Despite great progress being made during the last two decades in cardiovascular disease prevention, especially by lowering low-density lipoprotein-cholesterol with statins, cardiovascular events continue to occur. Plasma high-density lipoprotein (HDL) exerts multiple protective effects on the arterial wall, through promotion of reverse cholesterol transport, prevention of endothelial dysfunction and inhibition of lipid oxidation. Therapeutic interventions raising plasma HDL levels or directly mimicking its beneficial effects represent the next frontier in the prevention and treatment of cardiovascular disease.