The receptor for advanced glycation endproducts (RAGE) has been shown to play an important role in aging, neurodegeneration, diabetes, and inflammation. RAGE is a transmembrane receptor of the immunoglobuline superfamily, which recognizes a variety of ligands such as AGEs (advanced glycation endproducts), members of the S100/calgranulin family of proinflammatory mediators, β-sheet-fibrills, HMGB1 (amphoterin) and the 2-integrin Mac-1. RAGE/ligand interactions induce oxidative stress and lead to an up-regulation of pro-inflammatory pathways involving the proinflammatory transcription factor NF-κB, increased expression of cytokines, chemokines, and adhesion molecules. These effects markedly propagate cellular dysfunction and cause perturbation in a diverse group of diseases, such as agerelated neurodegenerative disorders, atherosclerosis, diabetic vascular complications, tumors, and chronic inflammatory disease. In addition, RAGE may also interfere with differentiation processes, which are required during organ development. In this article, we have reviewed recent advances on RAGE and RAGE/ligand function in cell adhesion and inflammation based on findings from cell cultures, animal models, and human diseases. The potential for targeting the RAGE/ligand pathway as therapeutic strategy will be discussed.