Radiotherapy remains one of the primary treatment modalities for most malignancies. Biologically based improvements in the scheduling of conventional radiotherapy and treatment planning, innovations like conformal radiotherapy and intensity-modulated radiation therapy have considerably improved the targeting and effectiveness of radiation for treatment of solid tumors. These new radiotherapy technologies are also promising means of focusing the activation of anti-tumor gene therapy systems, as an approach to further improve radiotherapeutic treatment, particularly for tumors refractive to current therapies. Gene therapy vectors that express therapeutic genes following irradiation have been produced. Delivery of such vectors to the tumor allows temporal and spatial expression of the transgenes within the radiation field. Hypoxia is a physiological characteristic of solid tumors and an independent prognostic marker for poor radiation treatment outcome. Nevertheless, hypoxia has been exploited to drive therapeutic gene expression from gene therapy vectors delivered to solid tumors exhibiting significant areas of low oxygen tension. Radiation and hypoxia inducible gene therapy systems rely on the activation of gene promoters containing specific responsive elements. Recent studies have shown the potential to combine these elements, permitting either or both stimuli to drive therapeutic gene expression. Furthermore, transgene expression can be amplified and sustained using novel 'signal feedback' or recombination systems. Such innovations allow promising new strategies to improve radiation treatment outcome, particularly where tumor hypoxia is a predominant issue.