The receptor for advanced glycation end products (RAGE) is a central signaling molecule in the innate immune system and is involved in the onset and sustainment of the inflammatory response. RAGE belongs to a class of pattern recognition receptors that recognize common features rather than a specific ligand. Recent structural information on the extracellular portion (ectodomain) of RAGE shed new light on this unusual ability. X-ray crystallographic, NMR and biochemical data suggest that ligand binding is driven largely by electrostatic interactions between the positively charged surface of the ectodomain and negatively charged ligands. In this article, I propose a putative mechanism of RAGE ligand recognition of receptor activation.