High-density lipoprotein-cholesterol (HDL-C) is a continuous inverse cardiovascular risk factor. The mechanisms by which HDLs protect against atherosclerosis are multiple. The major effect is thought to be reverse cholesterol transport, the mechanism by which excess cellular cholesterol is returned to the liver for excretion in the bile. HDLs also have pleiotropic roles: they decrease inflammation, prevent low-density lipoprotein oxidation, vascular endothelial cell apoptosis and thrombosis, and improve vascular endothelial function. Recent studies suggest that nascent HDL particles are metabolized rapidly and that their components (Apo AI, cholesterol and phospholipids) are rapidly exchanged within lipoprotein classes. There are many causes of HDL-C deficiency. Using Mendelian randomization, several groups have concluded that many genetic forms of HDL deficiency do not increase cardiovascular risk. This raises the controversial issue of the causality of low HDL-C as a cardiovascular risk factor, rather than a marker of cardiovascular health. This is reflected in the importance of lifestyle in determining HDL-C levels. The treatment of low HDL-C remains controversial, in part because the only currently available effective medication, niacin, is relatively poorly tolerated and outcomes studies on cardiovascular disease prevention are still pending.