Hypoxia is a crucial factor in the tumor microenvironment (TME) of many cancers and influences tumor evolution and growth, metastatic progression, and finally therapeutic outcomes. Over the past decades, hypoxia-mediated cellular and molecular changes in the TME have been studied extensively, thereby novel treatment approaches have come up with better clinical outcomes. In this chapter, we specifically describe hypoxia-induced DNA damage responses including ATR/ATM signaling, single-strand break and double-strand break responses, and checkpoints activation leading to remodeling of the TME niche. In continuation, we discuss the several DNA damage repair pathways that are also getting compromised during the hypoxic condition. Furthermore, how hypoxia-induced genomic instabilities at a larger scale through replication stress, chromosomal aberrations, epigenetic modifications, alterations in miRNAs, telomere dysfunction, etc. add to the complexities of treatment resistance and promoting survival capacities has been discussed extensively. Finally, the current clinical developments augmented for targeting hypoxia-induced DNA damage response and DNA repair machinery to eliminate resistant populations have been provided. We have also discussed the synthetic lethality strategy to specifically target repair deficient hypoxic niches as well along with other promising therapeutic approaches. Thus, this chapter provides in-depth concise knowledge of hypoxia-induced DNA damage response and genomic instability that eventually invoke to formulate new research directions.