The interaction of glucose-modified and inflammation-promoting ligands with the receptor for advanced glycation end products (RAGE) is emerging as a central mechanism contributing to the diverse complications of diabetes. These ligands, particularly in oligomeric form, bind to RAGE and transduce intracellular signals. The consequences of this interaction, as elucidated in cultured cells and animal models, include upregulation of inflammatory and tissue-degradative pathways. Pharmacologic antagonism of RAGE may hold promise for the treatment of diabetic complications.