Glioblastoma (GB) is the most prevalent and lethal form of brain cancer, with a survival rate under 2 years after diagnosis. Despite multimodality treatments, recurrence is almost universal. This review discusses recent progress in understanding GB pathophysiology, focusing on glioma stem cells (GSCs), the tumor microenvironment, and epigenetic mechanisms. Therapeutic strategies include the standard of care (SOC) treatment and targeted therapies that interfere with signaling pathways involved in GB tumorigenesis and resistance. Immunotherapeutic approaches, such as checkpoint inhibitors, vaccines, CAR-modified NK or T cells, and oncolytic virotherapy, aim to enhance the immune response against GB. Nanotherapies and non-ionizing energies, such as laser interstitial thermal therapy and high/low intensity focused ultrasounds, are also explored. The review aims to discuss advances and limitations of current therapies and novel approaches under development or clinical trials. Key diagnostic criteria, incidence, risk factors, and response evaluation criteria are discussed, highlighting the challenges in assessing treatment response and progression. The role of GSCs, metabolic features, ion channels, epigenetics, and angiogenesis in GB progression is detailed, emphasizing the need for targeted therapies to target specific populations of cells and improve patient outcomes.Glioblastoma (GB) is the most prevalent and lethal form of brain cancer, with a survival rate under 2 years after diagnosis. Despite multimodality treatments, recurrence is almost universal. This review discusses recent progress in understanding GB pathophysiology, focusing on glioma stem cells (GSCs), the tumor microenvironment, and epigenetic mechanisms. Therapeutic strategies include the standard of care (SOC) treatment and targeted therapies that interfere with signaling pathways involved in GB tumorigenesis and resistance. Immunotherapeutic approaches, such as checkpoint inhibitors, vaccines, CAR-modified NK or T cells, and oncolytic virotherapy, aim to enhance the immune response against GB. Nanotherapies and non-ionizing energies, such as laser interstitial thermal therapy and high/low intensity focused ultrasounds, are also explored. The review aims to discuss advances and limitations of current therapies and novel approaches under development or clinical trials. Key diagnostic criteria, incidence, risk factors, and response evaluation criteria are discussed, highlighting the challenges in assessing treatment response and progression. The role of GSCs, metabolic features, ion channels, epigenetics, and angiogenesis in GB progression is detailed, emphasizing the need for targeted therapies to target specific populations of cells and improve patient outcomes.