This review discusses the role of hypoxia-inducible factors (HIFs) in cancer and their potential as therapeutic targets. HIFs are transcription factors that regulate cellular responses to low oxygen levels, playing a critical role in cancer progression by influencing angiogenesis, cell proliferation, and glucose metabolism. The study explores various HIF-targeting strategies, including HIF inhibitors, anti-angiogenic therapies, and hypoxia-activated prodrugs, highlighting their potential in disrupting cancer-related signaling pathways. The research also addresses challenges such as toxicity and the need for specificity, emphasizing the importance of ongoing clinical trials to evaluate the efficacy and safety of HIF-targeted therapies. The review covers the structure and physiology of HIFs, their regulation, and their roles in different cancers, including liver cancer, renal cell carcinoma, gastric cancer, and breast cancer. It discusses the impact of HIFs on tumor immune escape and immunotherapy resistance, as well as their involvement in drug resistance mechanisms. The article concludes by emphasizing the potential of HIF-targeted therapies in the development of novel cancer treatments.This review discusses the role of hypoxia-inducible factors (HIFs) in cancer and their potential as therapeutic targets. HIFs are transcription factors that regulate cellular responses to low oxygen levels, playing a critical role in cancer progression by influencing angiogenesis, cell proliferation, and glucose metabolism. The study explores various HIF-targeting strategies, including HIF inhibitors, anti-angiogenic therapies, and hypoxia-activated prodrugs, highlighting their potential in disrupting cancer-related signaling pathways. The research also addresses challenges such as toxicity and the need for specificity, emphasizing the importance of ongoing clinical trials to evaluate the efficacy and safety of HIF-targeted therapies. The review covers the structure and physiology of HIFs, their regulation, and their roles in different cancers, including liver cancer, renal cell carcinoma, gastric cancer, and breast cancer. It discusses the impact of HIFs on tumor immune escape and immunotherapy resistance, as well as their involvement in drug resistance mechanisms. The article concludes by emphasizing the potential of HIF-targeted therapies in the development of novel cancer treatments.