The management of acute hypoxemic respiratory failure frequently includes the use of supraphysiological fractions of inspired oxygen (FiO₂), which can be beneficial in the short-term but not without risks in the long-term, causing acute lung injury (ALI). Over the last few years, much attention has been devoted to the intracellular signaling transduction pathways that lead to hyperoxia-induced cell damage, particularly MAP kinase cascades. Identification of involved signaling molecules and understanding of the regulation of the main signal transduction pathways might provide the basis for improving the outcome of patients under high FiO₂ exposure through more effective therapeutic interventions. This review, which includes studies published from 1987 to 2015, presents an overview on recent progresses in the hyperoxia ALI field with special emphasis on potential therapeutic targets and clinical approaches based on the molecular mechanisms underlying hyperoxia-induced inflammation. Further studies are needed to gain deeper insight into controversial molecular mechanisms underlying hyperoxia-induced cell death, which may play a critical role in future pharmacological interventions, as well as into hyperoxia-induced cell damage, that could monitor and therefore prevent hyperoxia ALI.