Radiation therapy plays an important role in the management of a wide range of 
cancers. Besides innovations in the physical application of radiation dose, 
radiation therapy is likely to benefit from novel approaches exploiting 
differences in radiation response between normal and tumor cells. While ionizing 
radiation induces a variety of DNA lesions, including base damages and 
single-strand breaks, the DNA double-strand break (DSB) is widely considered as 
the lesion responsible not only for the aimed cell killing of tumor cells, but 
also for the general genomic instability that leads to the development of 
secondary cancers among normal cells. Homologous recombination repair (HRR), 
non-homologous end-joining (NHEJ), and alternative NHEJ, operating as a backup, 
are the major pathways utilized by cells for the processing of DSBs. Therefore, 
their function represents a major mechanism of radiation resistance in tumor 
cells. HRR is also required to overcome replication stress - a potent 
contributor to genomic instability that fuels cancer development. HRR and 
alternative NHEJ show strong cell-cycle dependency and are likely to benefit 
from radiation therapy mediated redistribution of tumor cells throughout the 
cell-cycle. Moreover, the synthetic lethality phenotype documented between HRR 
deficiency and PARP inhibition has opened new avenues for targeted therapies. 
These observations make HRR a particularly intriguing target for treatments 
aiming to improve the efficacy of radiation therapy. Here, we briefly describe 
the major pathways of DSB repair and review their possible contribution to 
cancer cell radioresistance. Finally, we discuss promising alternatives for 
targeting DSB repair to improve radiation therapy and cancer treatment.