Glioblastoma multiforme (GBM) is the most common adult primary brain tumor. Standard treatment includes surgery, radiotherapy (RT), and chemotherapy with Temozolomide (TMZ). Despite this protocol, GBM remains resistant and recurs frequently. Hypoxia within the tumor contributes to aggressive behavior by activating hypoxia-inducible factors (HIFs), which promote survival and resistance. Preclinical and clinical approaches aim to target hypoxia to improve GBM treatment outcomes. These include inhibiting HIF-1α and HIF-2α, reoxygenation strategies, and anti-angiogenic therapies. Inhibitors of HIF-1α and HIF-2α have shown promise in preclinical studies but face challenges in clinical translation. Reoxygenation methods like trans-sodium crocetinate and myo-inositol trispyrophosphate enhance oxygen delivery to hypoxic regions. Anti-angiogenic therapies, such as bevacizumab and SU1498, target vascularization but have limited efficacy and toxicity. Other strategies include anti-parasitic drugs and FLASH radiotherapy, which deliver high doses quickly to reduce normal tissue damage. GBM organoids provide a model to study hypoxia and its effects. Despite these advances, clinical translation remains limited by resistance, toxicity, and variability in patient responses. Hypoxia remains underexplored in GBM treatment, and integrating hypoxia into diagnosis and therapy could improve outcomes. Future research should focus on personalized approaches and better understanding of hypoxia's role in GBM progression.Glioblastoma multiforme (GBM) is the most common adult primary brain tumor. Standard treatment includes surgery, radiotherapy (RT), and chemotherapy with Temozolomide (TMZ). Despite this protocol, GBM remains resistant and recurs frequently. Hypoxia within the tumor contributes to aggressive behavior by activating hypoxia-inducible factors (HIFs), which promote survival and resistance. Preclinical and clinical approaches aim to target hypoxia to improve GBM treatment outcomes. These include inhibiting HIF-1α and HIF-2α, reoxygenation strategies, and anti-angiogenic therapies. Inhibitors of HIF-1α and HIF-2α have shown promise in preclinical studies but face challenges in clinical translation. Reoxygenation methods like trans-sodium crocetinate and myo-inositol trispyrophosphate enhance oxygen delivery to hypoxic regions. Anti-angiogenic therapies, such as bevacizumab and SU1498, target vascularization but have limited efficacy and toxicity. Other strategies include anti-parasitic drugs and FLASH radiotherapy, which deliver high doses quickly to reduce normal tissue damage. GBM organoids provide a model to study hypoxia and its effects. Despite these advances, clinical translation remains limited by resistance, toxicity, and variability in patient responses. Hypoxia remains underexplored in GBM treatment, and integrating hypoxia into diagnosis and therapy could improve outcomes. Future research should focus on personalized approaches and better understanding of hypoxia's role in GBM progression.