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Gene delivery has the potential to offer effective treatment to patients with life-threatening lung diseases such as cystic fibrosis, α1-antitrypsin deficiency and lung cancer. Phase I/II clinical trials have shown that, in principle, gene transfer to the lung is feasible and safe. However, gene expression from both viral and non-viral gene delivery systems has been inefficient. In addition to extra- and intracellular barriers, the host innate and acquired immune system represents a major barrier to successful gene transfer to the lung. Results from studies in experimental animals and clinical trials have shown that inflammatory, antibody and T cell responses can limit transgene expression duration and readministration of the gene transfer vector. We will review here how the development of pharmacological and/or immunological agents can modulate the host immune system and the limitations of these strategies. A better understanding of the immunological barriers which exist in the lung might allow for a more sustained expression of the transgene and importantly help overcome the problem of readministration of viral vectors.