Receptor for AGE (RAGE), a member of the immunoglobulin superfamily, was first identified as a specific cell surface interaction site for Advanced Glycation Endproducts, or AGEs. AGEs, the products of nonenzymatic glycation/oxidation of proteins/lipids, accumulate in natural aging and disorders such as diabetes, renal failure and amyloidoses. Interaction of AGEs with RAGE has been linked to chronic inflammatory and vascular dysfunction that characterizes the chronic complications of these disorders. Recent studies have indicated that RAGE is a multiligand receptor, serving as a specific cell surface, signal transducing receptor for amphoterin, a molecule with implications for neurite outgrowth in neuronal development and in tumor cell proliferation and spread. RAGE is also a receptor for amyloid-beta peptide, whose interaction with neuronal and microglial RAGE within the CNS is linked to sustained inflammation and neuronal toxicity and cell death. RAGE also serves as a signal-transducing receptor for EN-RAGEs, and related members of the S100/calgranulin family of proinflammatory cytokines; consequences of this interaction include initiation and propagation of inflammatory responses. Consistent with an important role for ligand-RAGE interaction in these settings, blockade of RAGE suppresses chronic cellular activation and dysfunction in murine models of diabetic complications, inflammation and tumor proliferation and metastasis. Taken together, an new paradigm is emerging which links RAGE, a gene encoded within the Major Histocompatibility Complex (MHC) Class III regions, to central host response mechanisms in homeostasis and chronic disease.