Using elegant targeting techniques such as IMRT, radiation oncology has improved the therapeutic ratio of prostate cancer radiotherapy through increased physical precision (e.g. increased local control through dose-escalation without increased normal tissue toxicity). The therapeutic ratio might be further improved by the addition of "biologic precision and escalation" pertaining to the use of molecular inhibitors of DNA damage sensing and repair. Indeed, proteins involved in the ATM-p53 damage signaling axis and the homologous (HR) and non-homologous end-joining (NHEJ) pathways of DNA double-strand break (DNA-dsb) rejoining pathways may be attractive candidates to elucidate cancer risk, prognosis, prediction of response and to develop sensitizers towards oxic and hypoxic prostate tumor cells. This review highlights DNA-dsb in prostate cancer research in terms of novel molecular inhibitors, the role of the microenvironment in DNA-dsb repair and potential DNA-dsb biomarkers for clinical trials.