The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor (PRR) that interacts with diverse endogenous ligands. Ligation of RAGE triggers a series of cellular signaling events, including the activation of transcription factor NF-κB, leading to the production of pro-inflammatory cytokines, and causing inflammation. While acute inflammation serves to resolve pathogen infection and stresses, which promote tissue repair, persistent inflammation results in maladaptive tissue remodeling and damage. RAGE signaling has been implicated in multiple detrimental human illnesses including diabetes, atherosclerosis, arthritis, and Alzheimer's disease. In addition, prolonged inflammation often serves as the precursor for arterial remodeling that underlies the exponential increase of age-associated arterial diseases. Despite the significant progress and exciting discoveries in RAGE research, little is known on the biochemistry of RAGE and the signaling mechanism of RAGE remains poorly defined. The biological impact of RAGE signaling in clinical situations and aging-associated diseases also remains to be fully realized. This review attempts to provide a comprehensive summary on both recent findings and missing pieces of the RAGE puzzle.