Rationale: Hypoxia regulates the inflammatory/anti-inflammatory balance via the receptor for advanced glycation end products (RAGE), a versatile sensor of damage-associated molecular patterns. The multi-ligand nature of RAGE places this receptor in the midst of chronic inflammatory diseases. Objective: To characterize the impact of the hypoxia/RAGE pathway on pathogenic airway inflammation preventing effective pathogen clearance in Cystic Fibrosis (CF) and elucidate the potential role of this danger signal in pathogenesis and therapy of lung inflammation. Methods: We employed in vivo and in vitro models to study the impact of hypoxia on RAGE expression and activity in human and murine CF, the nature of the RAGE ligand and the impact of RAGE on lung inflammation and antimicrobial resistance in fungal and bacterial pneumonia. Main results: Sustained expression of RAGE and its ligand S100B was observed in murine lung and human epithelial cells and exerted a proximal role in promoting inflammation in murine and human CF, as revealed by functional studies and analysis of the genetic variability of AGER in patients with CF. Both hypoxia and infections contributed to the sustained activation of the S100B/RAGE pathway, being RAGE up-regulated by hypoxia and S100B by infection via Toll-like receptors. Inhibiting the RAGE pathway in vivo with soluble (s)RAGE reduced pathogen load and inflammation in experimental CF while sRAGE production was defective in CF patients. Conclusions: A causal link between hyper-activation of RAGE and inflammation in CF has been observed, such that targeting pathogenic inflammation alleviated inflammation in CF and measurement of sRAGE levels could be a useful biomarker for RAGE-dependent inflammation in CF patients.