RAGE was first discovered as a signal transduction receptor for Advanced Glycation Endproducts (AGEs). The identification of RAGE’s multi-ligand nature, and its intimate role in the inflammatory response, however, places RAGE at multiple points in the pathogenesis of type 1 diabetes – and its end-organ damage. (Auto)immune attack at the pancreatic β-cell leads to infiltration of inflammatory cells and increased expression/release of S100/calgranulins and HMGB1. Such ligands target RAGE in the islet and contribute to destruction and, ultimately, hyperglycemia. Hyperglycemia triggers rapid generation of AGEs, thereby recruiting RAGE in target organs via the micro- and macrovasculature. One component of RAGE’s action in target organs is the infiltration of inflammatory cells as well as end-organ stress – processes leading to release of S100/calgranulin and HMGB1. These ligands, together with AGEs, damage such cells as podocytes, endothelial and smooth muscle cells, Muller cells of the retina, cardiomyocytes, and central and peripheral nervous system neurons. Chronic inflammatory signaling, may, we predict, feed back to further damage the pancreatic islet and eliminate the possibility of regeneration. Stopping the cycle of RAGE action in inflammation and diabetes may be a novel form of therapy in this disorder and its complications.