This chapter discusses gene therapy and its use in mitigating pulmonary pathology involving acute or chronic lung injury. Strategies of gene transfer can be directed at genomic integrated long-term (permanent) expression, long-term nonintegrated expression, or short-term nonintegrated expres- sion. Gene therapy is unique among clinical interventions in that it has the potential to generate a prolonged effect at the cellular level that is not subject to pathways of excretion that affect traditional pharmacologic agents. Conversely, gene therapy presents unique challenges in terms of its development and application. This chapter discusses the scope of poten- tial gene-based therapies for lung injury, and the advantages and disadvan- tages of common delivery systems including viral vectors, liposomes or polymer encapsulation, and naked DNA. Current preclinical research and clinical trials of gene therapy for inflammatory, fibrotic, and immune diseases are reviewed, and specific practical examples of gene therapy are presented. Future directions for this evolving and exciting field are also outlined.