Glioblastoma (GB) is the most common and aggressive primary brain tumor, with poor prognosis despite advances in treatment. The Stupp protocol remains the standard of care (SOC) for newly diagnosed GB (ndGB), offering improved survival rates. GB recurs frequently, with survival under 2 years post-diagnosis. Recent research highlights the role of glioma stem cells (GSCs), the tumor microenvironment, and epigenetic mechanisms in GB progression. Therapeutic strategies include SOC treatments, targeted therapies targeting signaling pathways, and immunotherapies such as checkpoint inhibitors, vaccines, and CAR-modified T/NK cells. Nanotherapies and non-ionizing radiation (e.g., laser, ultrasound, photodynamic therapy) are also being explored. Challenges include GSC resistance, BBB barriers, and treatment resistance. Epigenetic alterations, such as DNA methylation and histone modifications, play a key role in GB progression. HDAC inhibitors and PRMT5 inhibitors are being tested for GB treatment. Angiogenesis and vasculogenic mimicry are critical for GB growth and resistance. Despite advances, GB remains highly treatment-resistant, with limited progress in improving survival. New therapies, including immunotherapy and nanotherapies, are under development to address these challenges.Glioblastoma (GB) is the most common and aggressive primary brain tumor, with poor prognosis despite advances in treatment. The Stupp protocol remains the standard of care (SOC) for newly diagnosed GB (ndGB), offering improved survival rates. GB recurs frequently, with survival under 2 years post-diagnosis. Recent research highlights the role of glioma stem cells (GSCs), the tumor microenvironment, and epigenetic mechanisms in GB progression. Therapeutic strategies include SOC treatments, targeted therapies targeting signaling pathways, and immunotherapies such as checkpoint inhibitors, vaccines, and CAR-modified T/NK cells. Nanotherapies and non-ionizing radiation (e.g., laser, ultrasound, photodynamic therapy) are also being explored. Challenges include GSC resistance, BBB barriers, and treatment resistance. Epigenetic alterations, such as DNA methylation and histone modifications, play a key role in GB progression. HDAC inhibitors and PRMT5 inhibitors are being tested for GB treatment. Angiogenesis and vasculogenic mimicry are critical for GB growth and resistance. Despite advances, GB remains highly treatment-resistant, with limited progress in improving survival. New therapies, including immunotherapy and nanotherapies, are under development to address these challenges.