Dysfunction of the surfactant system of the lung in the setting of acute lung injury (ALI) is likely to contribute to the pathophysiology of that syndrome. Multiple mechanisms, including injury to alveolar type II cells and inhibition by plasma proteins contribute to this loss of function. Similar injury occurs in animal models of acute lung injury and, in that setting, treatment with exogenous surfactant causes marked improvement in gas exchange. Clinical studies of surfactant treatment of ALI suggest benefit, and definitive phase III trials are now in progress.