Gene therapy for pulmonary disease has attracted a great deal of attention since the first report of successful gene delivery 10 years ago. Potential indications for gene therapy include chronic illnesses such as cystic fibrosis and alpha(1)-antitrypsin deficiency, and acute illnesses such as acute transplant rejection and chemotherapy-induced lung injury. The key technological impediment to successful gene therapy is vector optimization. Viral vectors, including adenovirus and adeno-associated virus, have relatively low efficiency in vivo. In addition, adenovirus has been associated with a brisk inflammatory response and limited duration of expression in the lung. Nonviral vectors, particularly liposomes, have also been tried, with limited expression efficiency and some toxicity. Although work is ongoing to improve adenoviral and adeno-associated viral vectors and test other viral and nonviral vectors, an ideal vector has not yet been identified. Several important barriers to successful gene therapy, including the host inflammatory response, promotor down-regulation, tissue-specific targeting, and physical barriers to gene delivery in the airway, will need to be overcome. Despite these daunting problems, several human gene therapy trials have been completed, using adenovirus, adeno-associated virus, and liposomes. In general, these trials have been focused on safety, and have shown that there is dose-dependent inflammation in response to adenovirus. Adeno-associated virus appears to cause little inflammation. Demonstration of successful gene delivery and transcription has been quite variable in human trials. In general, the level of expression of transgene appears to be quite low. In summary, although there is great promise for gene therapy in the lung, significant challenges remain in translating this technology to successful human therapy.