Gene therapy combined with radiotherapy represents a new approach for cancer treatment to selectively radiosensitize malignant cells or protect normal tissues. Examples of gene therapy strategies that modify the biological response to radiation include cytokine-mediated gene therapy and virally directed enzyme/pro-drug therapy (VDEPT). We have proposed the concept of gene therapy targeted by ionizing radiation, whereby a cDNA encoding a cytotoxin or an immunogenic protein that modifies the cellular radiation response is ligated downstream from a radiation inducible promoter. Protein is thus induced in response to irradiation. In this way, radiation acts as a molecular switch to activate transcription of a therapeutic gene. VDEPT incorporates a viral vector system to deliver a gene encoding a pro- drug activating enzyme to malignant cells. After intracellular expression of the enzyme, a nontoxic prodrug is converted to an active compound to selectively sensitize tumor cells to radiation. We will review current concepts of gene therapy and the studies that show its potential efficacy in the modification of radiation response.