The receptor for advanced glycation end products (RAGE) is a multiligand receptor that is expressed at high levels in the lungs. The emerging concept of pattern recognition involves RAGE and Toll-like receptors (TLRs) in sensing not only "pathogen-associated molecular patterns" (PAMPs) but also (endogenous) damage-associated molecular patterns (DAMPs). Infection is associated with the release of these endogenous proteins, such as high-mobility group box-1 (HMGB1) and S100A12. Engagement of RAGE by its diverse ligands results in receptor-dependent signaling and activation of NF-kappaB. Furthermore, RAGE acts as an endothelial adhesion receptor for leukocyte integrins and promotes leukocyte recruitment. Inhibition of RAGE signaling reduces inflammatory responses in several (non-infectious) models as well as in infectious models of cecal ligation and puncture and S. pneumoniae pneumonia. Importantly, RAGE signaling inhibition increased bacterial outgrowth and dissemination in an E. coli abdominal sepsis model. This review describes experimental studies that provide further insight into the role of RAGE and its ligands in host defense during clinically important infections, which eventually may contribute to better therapies against specific pathogens.