The development and progression of cancer is marked by the acquisition of specific genetic hallmarks that endow tumour cells with a survival advantage over their normal tissue counterparts. In the process, tumours frequently develop resistance to radiotherapy and chemotherapy, and acquire the ability to evade the host immune response. Cancer gene therapy (CGT) represents an ideal therapeutic tool to target one or more of these underlying genetic abnormalities, and restore some form of order, to the otherwise autonomous and discordant microenvironment of the tumour. Most of the current research in CGT is aimed at its development as a novel form of targeted therapy that can be combined with other treatment modalities such as radiotherapy and chemotherapy. CGT may be integrated into radical chemoradiotherapy regimens, with the rationale of optimising the therapeutic index, through selective enhancement of radiosensitivity and cytotoxicity in tumour compared to normal tissues. CGT strategies have been developed that are aimed at enhancing the radiosensitivity of tissues by targeting angiogenesis, silencing abnormal cellular signalling, restoration of apoptosis, and promotion of immune detection and destruction of tumour cells. In addition, cytotoxic approaches such as virus directed enzyme prodrug therapy (VDEPT), genetic radionuclide therapy (GRANT) and oncolytic viral therapy have been combined with radiation to augment the cumulative tumour cell kill and overall therapeutic effect. In this article, we discuss various CGT strategies that have been investigated in combination with radiation. All the available preclinical and clinical evidence is reviewed with special emphasis on strategies that have already found their way into the clinic, or those with significant translational potential for the future.