The receptor for advanced glycation end products (RAGE) is a multiligand cell-surface protein and belongs to the immunoglobulin superfamily. RAGE is expressed by different cell types, including macrophages, lymphocytes, endothelial, neuronal, and smooth muscle cells. In addition to advanced glycation end products (AGEs), RAGE binds amphoterin, S100/calgranulin, amyloid, transthyretin, and a leukocyte integrin, Mac-1. Engagement of RAGE in intracellular signaling leads to the activation of the proinflammatory transcription factor NF-kappaB to sustained cellular dysfunction and tissue destruction. In this study a pivotal role of RAGE in the progression of various diseases, i.e. diabetes, inflammation, neurodegeneration, tumors, vascular injury, atherosclerosis, and septic shock, is presented.