When invaded by pathogens, host defense systems encounter PAMPs from microorganisms and DAMPs that are released from tissues, which are recognized by TLRs and NLRs to warn the host of imminent danger. In addition, the multiligand receptor for advanced glycation endproducts (RAGE) is regarded as a prototypic DAMP receptor that can bind several DAMPs, including HMGB1 and S100A12 [6] . Other known RAGE ligands include amyloid, β-sheet fi brils, S100B and S100P [7] ; furthermore, β2 integrins can interact with RAGE [8] . RAGE is expressed at high levels in the lungs and at low levels in normal adult tissues, including on cells involved in the innate immune system, e.g., neutrophils, T and B lymphocytes, monocytes, macrophages, dendritic cells, and endothelial cells [7] . Engagement of RAGE by its ligands leads to receptor-dependent signaling and activation of NF-κB and mitogen-activated protein kinase (MAPK) pathways [7] . Activation of RAGE plays a role in diverse experimentally-induced sterile infl ammatory and infectious diseases, including cecal ligation and puncture (CLP)-induced abdominal sepsis [9] , diabetic nephropathy, delayed type hypersensitivity, type II collagen induced arthritis, hepatic injury, and diabetic atherosclerosis [7, [10] [11] [12] . Th is review focuses on new insights into the pathogenesis of infectious diseases, including sepsis, peritonitis and pneumonia, off ered by studies conducted in the RAGE research fi eld. 