The low-density lipoprotein (LDL) receptor-related protein (LRP) is a member of the LDL receptor family. In addition to its role in endocytosis and uptake of multiple ligands, it is now apparent that LRP, like some other members of the family, is also involved in signal transduction. Through LRP, both endocytosis and signaling coexist at the surface of the plasma membrane and regulate critical cellular physiology and signal transduction events. This article focuses on the recently uncovered molecular mechanisms by which LRP, its ligand apolipoprotein E, and the platelet-derived growth factor receptor cooperate in the remodeling of the vascular wall and protect against atherosclerosis.