Improving local tumor control is a goal of modern radiotherapy that will directly impact a majority of cancer patients. Numerous attempts to develop radiosensitizing agents have, however, met with limited clinical success. Recent advances in gene therapeutic approaches have allowed researchers to combine gene therapy with ionizing radiation to enhance tumor cell killing. In the following review, we discuss the current advances in the use of radiation-inducible promoters, the use of pro-drug converting enzymes, and cytotoxic cytokines to enhance the therapeutic efficacy of ionizing radiation.