Mesothelioma represents an especially good target for gene therapy since few effective therapies exist, the disease remained relatively localized until late in its course, the tumor can be accessed relatively easily through the chest wall, and the thin layer of mesothelial cells offers a large surface area for efficient, rapid, and diffuse gene transfer. Gene therapy trials in mesothelioma have shown safety, and some limited evidence of efficacy. We present a review of clinical trials that have been performed in mesothelioma and describe several new approaches currently being pursued.