High-density lipoprotein (HDL) plays an important role in protection against atherosclerosis. A major part of HDL’s antiatherogenic role is through mediating reverse cholesterol transport from peripheral cells, such as macrophages and other cells in the artery wall, to the liver. Hepatic HDL receptors should, therefore, play an important role in either mediating or modulating HDL-dependent reverse cholesterol transport. The scavenger receptor class B type I (SR-BI) was first identified as a hepatic HDL receptor almost 10 years ago and is well characterized at the molecular level. This review highlights recent studies that provide insight into the cellular pathways involved in SR-BI-mediated lipid transfer between bound lipoproteins and cells, supports a role for this receptor in reverse cholesterol transport and protection against experimental atherosclerosis in mice, and explores the consequences of sequence variations in the gene encoding SR-BI in humans.