Delivery of therapeutic genes to the lungs is an attractive strategy to correct a variety of pulmonary dysfunctions such as cystic fibrosis, alpha-1 antitrypsin deficiency, pulmonary hypertension, asthma, and lung cancer. Different delivery routes such as intratracheal instillation, aerosol and intravenous injection have been utilized with varying degrees of efficiency. Both viral and non-viral vectors, with their respective strengths and weaknesses, have achieved significant levels of transgene expression in the lungs. However, the application of gene therapy for the treatment of pulmonary disease has been handicapped by various barriers to the delivery vectors such as serum proteins during intravenous delivery, and surfactant proteins and mucus in the airway lumen during topical application of therapeutic genes. Immune and cytokine responses against the delivery vehicle are also major problems encountered in pulmonary gene therapy. Despite these shortcomings much progress has been made to enhance the efficiency, as well as lower the toxicity of gene therapy vehicles in the treatment of pulmonary disorders such as cystic fibrosis, lung cancer and asthma.