The HDL receptor scavenger receptor class B type I plays an important role in meditating the uptake of HDL-derived cholesterol and cholesteryl ester in the liver and steroidogenic tissues. However, the mechanism by which scavenger receptor class B type I mediates selective cholesterol uptake is unclear. In hepatocytes scavenger receptor class B type I mediates the transcytosis of cholesterol into bile, appears to be expressed on both basolateral and apical membranes, and directly interacts with a PDZ domain containing protein that may modulate the activity of scavenger receptor class B type I. This suggests the involvement of scavenger receptor class B type I in higher order complexes in polarized cells. Scavenger receptor class B type I expression has been shown to alter plasma membrane cholesterol distribution and induce the formation of novel membrane structures, suggesting multiple roles for scavenger receptor class B type I in the cell. A close examination of scavenger receptor class B type I function in polarized cells may yield new insights into the mechanism of scavenger receptor class B type I-mediated HDL selective uptake and the effects of scavenger receptor class B type I on cellular cholesterol homeostasis.