Tumor hypoxia is a major contributor to resistance to anti-cancer therapies. Given that the results of hypoxia-targeted therapy trials have been disappointing, a more personalized approach may be needed. Here we characterize multi-OMIC molecular features associated with tumor hypoxia and identify molecular alterations that correlate with both drug-resistant and drug-sensitive responses to anti-cancer drugs. Based on a well-established hypoxia gene expression signature, we classify about 10,000 tumor samples into hypoxia score-high and score-low groups across different cancer types from The Cancer Genome Atlas and demonstrate their prognostic associations. We then identify various types of molecular features associated with hypoxia status that correlate with drug resistance but, in some cases, also with drug sensitivity, contrasting the conventional view that hypoxia confers drug resistance. We further show that 110 out of 121 (90.9%) clinically actionable genes can be affected by hypoxia status and experimentally validate the predicted effects of hypoxia on the response to several drugs in cultured cells. Our study provides a comprehensive molecular-level understanding of tumor hypoxia and may have practical implications for clinical cancer therapy.