At high levels as seen in diabetes, glucose reacts with and forms adducts (advanced glycation end products; AGEs) on macromolecules including proteins and DNA, eliciting cellular dysfunction and leading to vascular disease. The major means is through cellular receptors; the best characterized is the receptor for advanced glycation end products (RAGE). Accumulation of both AGE/RAGE in addition to other identified ligands of RAGE, including S100/calgranulins, is the hallmark of this receptor in disease pathogenesis. Blockade of ligand-receptor interaction directly at the protein level, or transgenetically, prevents development of micro vascular (nephropathy) and macro vascular (atherosclerosis/restenosis) disease in small animal models. Furthermore, allelic variants of RAGE exist that alter the protein function and gene expression, which may further affect disease outcome. In conclusion, RAGE is a target for drug development to prevent vascular disease in diabetic and nondiabetic subjects.