Lung alveolar epithelial cells are normally very well oxygenated, but may be exposed to hypoxia in many pathological conditions such as pulmonary edema, acute respiratory distress syndrome, chronic obstructive pulmonary diseases, or in some environmental conditions such ascent to high altitude. The ability of alveolar epithelial cells to cope with low oxygen tensions is crucial to maintain the structural and functional integrity of the alveolar epithelium. Alveolar epithelial cells appear to be remarkably tolerant to oxygen deprivation as they are able to maintain adequate cellular ATP content during prolonged hypoxic exposure when mitochondrial oxidative phosphorylation is limited. This property mostly relies on the ability of the cells to rapidly modify their gene expression program, stimulating the expression of genes involved in anaerobic energy supply and repressing expression of genes involved in some ATP-consuming cellular processes. This adaptive strategy of the cells is mostly - but not entirely - dependent on the expression of Hypoxia-Inducible Factors (HIFs), known to be responsible for orchestrating a large number of hypoxia-sensitive genes. This review focuses on the role of hypoxia-inducible factor isoforms expressed in alveolar epithelial cells exposed to hypoxia, and on the specific hypoxic gene regulation which takes place in alveolar epithelial cells either through HIF-dependent or independent pathways.