ALI/ARDS may be suitable for gene-based therapies as it is an acute but relatively transient process [8] , requiring short-lived gene expression, obviating the need for repeated therapies and reducing the risk of an adverse immunological response. Th e distal lung epithelium is selectively accessible via the tracheal route of administration, allowing targeting of the pulmonary epithelium [9] . Th e pulmonary vasculature is also relatively accessible, as the entire cardiac output must transit this circulation. Antibodies that bind antigens selectively expressed on the pulmonary endothelial surface can be complexed to gene vectors to facilitate selective targeting following intravenous administration [10] . It is also possible to use gene-based strategies to target other cells central to the pathogenesis of ALI/ARDS, such as leuko cytes and Abstract Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) confer substantial morbidity and mortality, and have no specifi c therapy. The accessibility of the distal lung epithelium via the airway route, and the relatively transient nature of ALI/ ARDS, suggest that the disease may be amenable to gene-based therapies. Ongoing advances in our understanding of the pathophysiology of ALI/ARDS have revealed multiple therapeutic targets for genebased approaches. Strategies to enhance or restore lung epithelial and/or endothelial cell function, to strengthen lung defense mechanisms against injury, to speed clearance of infection and to enhance the repair process following ALI/ARDS have all demonstrated promise in preclinical models. Despite three decades of gene therapy research, however, the clinical potential for gene-based approaches to lung diseases including ALI/ ARDS remains to be realized. Multiple barriers to eff ective pulmonary gene therapy exist, including the pulmonary architecture, pulmonary defense mechanisms against inhaled particles, the immunogenicity of viral vectors and the poor transfection effi ciency of nonviral delivery methods. Defi cits remain in our knowledge regarding the optimal molecular targets for genebased approaches. Encouragingly, recent progress in overcoming these barriers off ers hope for the successful translation of gene-based approaches for ALI/ARDS to the clinical setting. fi bro blasts [11] . Furthermore, gene-therapy-based approaches off er the potential to selectively target diff erent phases of the injury and repair process. Th e potential to target specifi c aspects of the injury and repair processes such as epithelial-mesenchymal transition, fi brosis, fi brinolysis, coagulopathy and oxidative stress with these approaches is also clear.