The article reviews the impact of oxygen (O2) availability on human cancer, focusing on the role of hypoxia and hypoxia-inducible factors (HIFs). Hypoxia, defined as reduced O2 levels, is a common feature in solid tumors, leading to altered cellular metabolism, increased resistance to radiation and chemotherapy, and enhanced angiogenesis and metastasis. Early observations by Otto Warburg in the 20th century highlighted that tumor cells favor glycolysis regardless of O2 levels, but subsequent research has revealed more complex mechanisms involving HIFs. HIFs are heterodimeric transcription factors consisting of an α and a β subunit. HIF-1α, identified in the 1990s, plays a central role in mediating the cellular response to hypoxia. HIF-1α is rapidly induced by hypoxia, binds to hypoxia response elements (HREs) in the promoter regions of target genes, and regulates genes involved in angiogenesis, metabolism, proliferation, and autophagy. HIF-2α and HIF-3α also exist but have different tissue-specific expression patterns and functions. The article discusses the therapeutic implications of HIFs, including the development of drugs that target HIFs or its downstream targets. Bevacizumab, a monoclonal antibody against VEGF, is an example of a drug that inhibits angiogenesis and has shown clinical benefits in various cancers. Other strategies, such as targeting HIF accumulation or inhibiting key HIF target genes, are also being explored. The identification of HIFs and their downstream targets has opened new avenues for the development of targeted therapies. However, challenges remain, including the need for more precise and non-invasive methods to measure O2 levels in tumors and the understanding of HIF-independent pathways that respond to hypoxia. The article concludes by highlighting the importance of further research to improve the treatment of cancer and overcome therapeutic resistance induced by hypoxia.The article reviews the impact of oxygen (O2) availability on human cancer, focusing on the role of hypoxia and hypoxia-inducible factors (HIFs). Hypoxia, defined as reduced O2 levels, is a common feature in solid tumors, leading to altered cellular metabolism, increased resistance to radiation and chemotherapy, and enhanced angiogenesis and metastasis. Early observations by Otto Warburg in the 20th century highlighted that tumor cells favor glycolysis regardless of O2 levels, but subsequent research has revealed more complex mechanisms involving HIFs. HIFs are heterodimeric transcription factors consisting of an α and a β subunit. HIF-1α, identified in the 1990s, plays a central role in mediating the cellular response to hypoxia. HIF-1α is rapidly induced by hypoxia, binds to hypoxia response elements (HREs) in the promoter regions of target genes, and regulates genes involved in angiogenesis, metabolism, proliferation, and autophagy. HIF-2α and HIF-3α also exist but have different tissue-specific expression patterns and functions. The article discusses the therapeutic implications of HIFs, including the development of drugs that target HIFs or its downstream targets. Bevacizumab, a monoclonal antibody against VEGF, is an example of a drug that inhibits angiogenesis and has shown clinical benefits in various cancers. Other strategies, such as targeting HIF accumulation or inhibiting key HIF target genes, are also being explored. The identification of HIFs and their downstream targets has opened new avenues for the development of targeted therapies. However, challenges remain, including the need for more precise and non-invasive methods to measure O2 levels in tumors and the understanding of HIF-independent pathways that respond to hypoxia. The article concludes by highlighting the importance of further research to improve the treatment of cancer and overcome therapeutic resistance induced by hypoxia.