Radiotherapy (RT) is a primary treatment modality for the majority of solid tumors. The objective is to destroy the tumor mass by exposure to ionizing radiation (IR) from an external beam or isotopic source. IR causes DNA damage directly and indirectly via the production of reactive oxygen intermediates (ROIs). Accumulation of sufficient damage leads to tumor cell death. The efficacy of RT is usually governed by the radiation dose given, the main limitation being the need to avoid injury to the surrounding normal tissues. To address the latter problem, physical techniques such as conformal and intensity-modulated radiotherapy have been developed to improve the precision of dose delivery to the tumor volume. However, some tumors prove refractory to conventional radiotherapy treatments, as insufficient dose can be delivered to the tumor. In such cases, other therapeutic strategies, such as chemotherapy, can be used in combination, particularly if such drugs lead to increased tumor radiosensitization. Nevertheless, many tumor types, (e.g., glioblastoma) are often resistant to even these combined approaches. Consequently, there is a need for new strategies that can improve the effectiveness of current radiotherapy regimens. Gene therapy offers the exciting possibility of significantly improving the efficacy of radiotherapy without the need for IR-dose escalation or undue increases in normal tissue morbidity. Furthermore, the potential to spatially and temporally target the activation of gene therapy vectors using clinically relevant IR doses provides a particularly attractive prospect.