Altering the genetic makeup of a cancer cell by gene transfer is a potentially powerful strategy for treating human cancer. However, a low efficiency of gene delivery in vivo and poor tumor specificity has prevented the widespread implementation of this technology in the clinic. Despite these formidable obstacles, the first successful application of gene therapy in the treatment of cancer could occur when it is combined with local modalities such as radiation therapy. A small number of gene therapy strategies have been evaluated in clinical trials in combination with external-beam radiation therapy. Combined therapy has been well tolerated and has not exacerbated the side effects of radiation therapy. Gene transfer and tumor cell destruction have been demonstrated in vivo. Although the results await confirmation in larger, prospective phase III trials, there is suggestive evidence that combined therapies may be demonstrating better than expected antitumor activity. The vast knowledge of the molecular defects that drive the cancer process, coupled with expanding the understanding of the genes responsible for tumor cell radioresistance, have led to the development of rational, targeted gene therapies designed to increase tumor cell radiosensitivity. Results of the clinical trials conducted to date are reviewed, followed by a description of new approaches currently under development.