Radiotherapy is very effective in local control of cancerous tumors, but its curative potential is often limited by intrinsic radioresistance of the tumor cells. Since DNA repair pathways remove radiation-induced DNA lesions and protect cells from lethality, these pathways represent potential therapeutic targets to radiosensitize tumors. In order to achieve a therapeutic gain, however, there must be a differential between tumor and normal cells that can be exploited to preferentially target the DNA repair of the tumor, while sparing surrounding normal tissues, and this has represented a significant challenge to progress. Nevertheless, recent advances in our understanding of DNA repair mechanisms and tumor biology, on both the biochemical and genetic levels, have identified molecular differentials that may increase tumor specificity. This mechanistic insight suggests new strategies for radiotherapeutic targeting of DNA repair. Some of these strategies are reviewed here, including synthetic lethal, replicative stress, cell cycle and hypoxia-based approaches. The example of PARP1 inhibitor use in BRCA1 and 2 mutated breast cancer therapy is discussed, and future directions and challenges are explored.