Many gene-therapy strategies under investigation aim to increase the efficacy of current cancer-treatment regimens. Promising results have been obtained in the laboratory and early clinical trials using viral-based motifs specifically designed to enhance the efficacy of ionizing radiation or chemotherapy. These strategies fall into two general categories: replication-incompetent viral shuttle vectors for the delivery of specific genes encoding a chemo/radiation modulator and attenuated replication-competent viruses with proposed replicative advantages in tumor cells. In this review, we discuss the rational, molecular mechanisms, and clinical application of these strategies with particular focus on recent research applying these viral-based strategies to improve the therapeutic index of ionizing radiation.