While chemotherapy and radiation therapy have been integral components of cancer management for decades, the issues of local recurrence, clinical resistance, and toxicities resulting from these treatment modalities have increased the interest in novel therapeutic approaches that could attenuate tumor progression and prevent recurrences. This Forum highlights current research focused on elucidation of the mechanisms of response to radiation treatment and the development of out-of-the-box therapeutic strategies for cancer treatment with radiation. Experts in the field of radiation research contribute with review articles describing the current knowledge on DNA damage response mechanisms, regulation of signaling involved in the DNA damage response by miRNA, the function of tumor hypoxia in tumor response to radiation, and the role of stem cells in protection of normal tissue against radiation damage.