About 30 years ago, John Glomset1 outlined the reverse cholesterol transport hypothesis, proposing that HDL and LCAT might have anti-atherogenic functions related to their ability to transport cholesterol from peripheral tissues to the liver for excretion. As the different molecules and pathways mediating the various steps of reverse cholesterol transport have been discovered, this hypothesis has been sustained and refined. Much remains to be learned, particularly in relation to molecular mechanisms, regulation, and metabolic integration of the different steps of reverse cholesterol transport. The plot is already thick but undoubtedly there are many new molecular players waiting in the wings. A particular challenge is to manipulate reverse cholesterol transport therapeutically in a way that will reduce atherosclerosis and its complications.