Current therapy such as radiation and chemotherapy controls less than 50% of lung cancers, summoning the development of novel therapeutic strategies that can directly target the underlying mechanisms of tumorigenesis. The clinical trials summarized in this article clearly demonstrate that contrary to initial predictions that gene therapy would not be suitable for cancer, gene replacement therapy is a viable potential addition to the arsenal for cancer. Gene expression has been documented and occurs even in the presence of an antiadenovirus immune response. Clinical trials have demonstrated that direct intratumor injection can cause tumor regression or prolonged stabilization of local disease, and the low toxicity associated with gene transfer indicates that tumor suppressor gene replacement can be readily combined with existing and future treatments. Initial concerns that the wide diversity of genetic lesions in cancer cells would prevent the application of gene therapy to cancer appear unfounded; on the contrary, correction of a single genetic lesion has resulted in significant tumor regression. Studies combining transfer of tumor suppressor genes with conventional DNA-damaging treatments indicate that correction of a defect in apoptosis induction can restore sensitivity to radiation and chemotherapy in some resistant tumors, and indications that sensitivity to killing might be enhanced in already sensitive tumors may eventually lead to reduced toxicity from chemotherapy and radiation therapy. The most recent data from the laboratory demonstrating damage to tumor suppressor genes in normal tissue and premalignant lesions even suggest that these genes may someday be useful in early intervention, diagnosis, and even prevention of cancer. Despite the obvious promise evident in the results of these studies, however, it is critical to recognize that there are still gaps in knowledge and technology to address. At the current rate of biotechnology development, it is only a matter of time until technical limitations that currently prevent the widespread application of gene therapy to cancer are overcome by development of more efficient vectors, discovery of novel genes, and development of combined modality approaches.