Acute lung injury (ALI) is a common, highly lethal acquired disorder that affects over one hundred thousand people each year and for which there are no specific therapies. Extensive investigations in experimental models and humans with ALI have identified several maladaptive host responses and dysregulated protein systems that offer therapeutic opportunities for genetic intervention. Several lines of evidence suggest that gene transfer can be used to deliver protective proteins that improve alveolar epithelial and/or endothelial cell function or immunomodulators that augment lung defense mechanisms and speed clearance of infection. In many instances, gene transfer is the only avenue for producing localized expression of these pharmaceuticals. This article reviews recent translational, animal-based studies that tested the use of gene and cell based therapies to ameliorate or prevent ALI. The lack of effective therapies for ALI and the approachability of the lung for local gene transfer suggest that ALI is a unique example of an acute disease process that is suitable for gene therapy.