A large body of clinical evidence exists to suggest that tumor hypoxia negatively impacts radiotherapy. As a result, there has been longstanding active research into novel methods of improving tumor oxygenation, targeting hypoxic tumor cells, and otherwise modulating the effect hypoxia has on how tumors respond to radiation. Over time, as more has been learned about the many ways hypoxia affects tumors, our understanding of the mechanisms connecting hypoxia to radiosensitivity has become increasingly broad and complicated. This has opened up new potential avenues for interrupting hypoxia's negative effects on tumor radiosensitivity. Here, we will review what is currently known about the spectrum of influence hypoxia has over the way tumors respond to radiation. Particular focus will be placed on recent discoveries suggesting that hypoxia-inducible factor-1 (HIF-1), a transcription factor that upregulates its target genes under hypoxic conditions, plays a major role in determining tumor radiosensitivity. HIF-1 and/or its target genes may represent therapeutic targets which could be manipulated to influence hypoxia's impact on tumor radiosensitivity.