Glioblastoma multiforme (GBM) is the most common adult primary brain tumor, and despite standard treatment including maximal surgical resection, radiotherapy (RT), and chemotherapy with Temozolomide (TMZ), it remains highly resistant and often recurs. Chronic hypoxia, a key factor in GBM's aggressive nature, is underappreciated in clinical management. This review discusses recent preclinical and clinical approaches to target tumor hypoxia, enhance GBM response to conventional therapies, and their results and limitations. **Preclinical Approaches:** 1. **Inhibition of HIF-1α and HIF-2α:** Several inhibitors have been synthesized to counteract hypoxia's impact, but their therapeutic specificity is debatable. 2. **Reoxygenation:** Compounds like trans-sodium crocetinate (TSC) and myo-inositol trisphosphate (ITPP) aim to increase oxygen delivery to hypoxic regions, showing promising results in preclinical studies. 3. **Targeting Angiogenesis:** Anti-VEGF therapies (e.g., bevacizumab) and integrin inhibitors (e.g., cilengitide) have shown mixed results in clinical trials. 4. **Inhibition of Cellular Oxygen Consumption:** Anti-parasitic drugs and metformin aim to reduce oxygen consumption, with some showing potential in preclinical studies. **Clinical Strategies:** 1. **Reoxygenation:** Hyperbaric oxygen therapy (HBOT) and carbogen-nicotinamide have shown mixed results in clinical trials. 2. **Targeting Angiogenesis:** Bevacizumab has been approved by the FDA but has shown limited benefits in clinical trials. 3. **Inhibition of Cellular Oxygen Consumption:** Metformin has shown safety but no significant improvement in OS in clinical trials. 4. **Hypoxia-Activated Prodrugs:** Evofosfamide is a promising prodrug that enhances diffusion into hypoxic regions, but its clinical efficacy is yet to be determined. **Limitations:** - Acquired resistance to inhibitors. - Tolerance and toxicity issues. - Lack of significant improvement in OS when combined with first-line treatments. - Some strategies are not yet integrated into clinical trials. **Conclusion:** Targeting hypoxia offers a promising approach to reverse GBM's aggressive behavior. Preclinical and clinical studies have explored various strategies, but challenges remain in translating these approaches into effective clinical treatments. Integrating hypoxia into the diagnosis and treatment of GBM could lead to better outcomes and personalized multimodal approaches.Glioblastoma multiforme (GBM) is the most common adult primary brain tumor, and despite standard treatment including maximal surgical resection, radiotherapy (RT), and chemotherapy with Temozolomide (TMZ), it remains highly resistant and often recurs. Chronic hypoxia, a key factor in GBM's aggressive nature, is underappreciated in clinical management. This review discusses recent preclinical and clinical approaches to target tumor hypoxia, enhance GBM response to conventional therapies, and their results and limitations. **Preclinical Approaches:** 1. **Inhibition of HIF-1α and HIF-2α:** Several inhibitors have been synthesized to counteract hypoxia's impact, but their therapeutic specificity is debatable. 2. **Reoxygenation:** Compounds like trans-sodium crocetinate (TSC) and myo-inositol trisphosphate (ITPP) aim to increase oxygen delivery to hypoxic regions, showing promising results in preclinical studies. 3. **Targeting Angiogenesis:** Anti-VEGF therapies (e.g., bevacizumab) and integrin inhibitors (e.g., cilengitide) have shown mixed results in clinical trials. 4. **Inhibition of Cellular Oxygen Consumption:** Anti-parasitic drugs and metformin aim to reduce oxygen consumption, with some showing potential in preclinical studies. **Clinical Strategies:** 1. **Reoxygenation:** Hyperbaric oxygen therapy (HBOT) and carbogen-nicotinamide have shown mixed results in clinical trials. 2. **Targeting Angiogenesis:** Bevacizumab has been approved by the FDA but has shown limited benefits in clinical trials. 3. **Inhibition of Cellular Oxygen Consumption:** Metformin has shown safety but no significant improvement in OS in clinical trials. 4. **Hypoxia-Activated Prodrugs:** Evofosfamide is a promising prodrug that enhances diffusion into hypoxic regions, but its clinical efficacy is yet to be determined. **Limitations:** - Acquired resistance to inhibitors. - Tolerance and toxicity issues. - Lack of significant improvement in OS when combined with first-line treatments. - Some strategies are not yet integrated into clinical trials. **Conclusion:** Targeting hypoxia offers a promising approach to reverse GBM's aggressive behavior. Preclinical and clinical studies have explored various strategies, but challenges remain in translating these approaches into effective clinical treatments. Integrating hypoxia into the diagnosis and treatment of GBM could lead to better outcomes and personalized multimodal approaches.