Th e innate immune response is the fi rst line of defense against pathogens. Th e experimental studies described herein 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 specifi c pathogens. While interpreting the results from preclinical investigations, one has to keep in mind that a careful balance between the infl amma tory and anti-infl ammatory response is vital in order to survive or recover from a severe infection.