Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is an acute life-threatening form of hypoxemic respiratory failure with a high mortality rate, and there is still a great need for more effective therapies for such a severe and lethal disease. Dysfunction of endothelial and epithelial barriers is one of the most important mechanisms in hypoxia-associated ALI/ARDS. The acceleration of the epithelial repair process in the injured lung may provide an effective therapeutic target. KGF-2, a potent alveolar epithelial cell mitogen, plays an important role in organ morphogenesis and epithelial differentiation, and modulates a variety of mechanisms recognized to be important in alveolar repair and resolution in ALI/ARDS. Preclinical and clinical studies have suggested that KGF-2 may be the candidate of novel therapies for alveolar epithelial damage during ALI/ARDS.