The receptor for advanced glycation endproducts (RAGE) is a member of the immunoglobulin superfamily of cell-surface molecules with a diverse repertoire of ligands. In the atherosclerotic milieu, three classes of RAGE ligands, i.e., products of non-enzymatic glycoxidation, S100 proteins and amphoterin, appear to drive receptor-mediated cellular activation and potentially, acceleration of vascular disease. The interaction of RAGE-ligands effectively modulates several steps of atherogenesis, triggering an inflammatory-proliferative process and furthermore, critically contributing to propagation of vascular perturbation, mainly in diabetes. RAGE has a circulating truncated variant isoform, soluble RAGE (sRAGE), corresponding to its extracellular domain only. By competing with cell-surface RAGE for ligand binding, sRAGE may contribute to the removal/neutralization of circulating ligands thus functioning as a decoy. The critical role of RAGE in the chronic vascular inflammation processes highlights this receptor-ligand axis as a possible and attractive candidate for therapeutic intervention to limit vascular damage and its associated clinical disorders.