Radiation, alkylating agents, and platinum-based chemotherapy treatments eliminate cancer cells through the induction of excessive DNA damage. The resultant DNA damage challenges the cancer cell's DNA repair capacity. Among the different types of DNA damage induced in cells, double-strand breaks (DSB) are the most lethal if left unrepaired. Unrepaired DSBs in tumor cells exacerbate existing gene deletions, chromosome losses and rearrangements, and aberrant features that characteristically enable tumor progression, metastasis, and drug resistance. Tumor microenvironmental factors like hypoxia, inflammation, cellular metabolism, and the immune system profoundly influence DSB repair mechanisms. Here, we put into context the role of the microenvironment in governing DSB repair mechanisms.