The HDL receptor scavenger receptor class B type I (SR-BI) plays crucial roles in cholesterol homeostasis, lipoprotein metabolism, and atherosclerosis. Hepatic SR-BI mediates reverse cholesterol transport (RCT) by the uptake of HDL cholesterol for routing to the bile. Through the selective uptake of HDL lipids, hepatic SR-BI modulates HDL composition and preserves HDL's atheroprotective functions of mediating cholesterol efflux and minimizing inflammation and oxidation. Macrophage and endothelial cell SR-BI inhibits the development of atherosclerosis by mediating cholesterol trafficking to minimize atherosclerotic lesion foam cell formation. SR-BI signaling also helps limit inflammation and cell death and mediates efferocytosis of apoptotic cells in atherosclerotic lesions thereby preventing vulnerable plaque formation. SR-BI is emerging as a multifunctional therapeutic target to reduce atherosclerosis development.