Glioblastoma, the most aggressive and common primary brain tumor, is characterized by infiltrative growth, abundant vascularization, and poor prognosis with a median survival of approximately 15 months. Despite technological advancements and improved understanding of its pathophysiology, significant progress has not been made in therapies or survival outcomes. Recent molecular profiling has led to a more refined classification of glioblastoma, identifying several genetic and epigenetic alterations, such as mutations in RTK/RAS/PI3K signaling pathways, p53, and RB, as well as IDH mutation, MGMT methylation, and 1p/19q codeletion. MicroRNAs like miR-10b and miR-21 have also been identified as prognostic biomarkers. Current treatment options include surgery, radiotherapy, and alkylating agent chemotherapy, with MGMT promoter methylation predicting benefit from temozolomide treatment. Targeted therapies based on intrinsic signaling pathways and antigenic profiles are under investigation. Liquid biopsies, including circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and extracellular vesicles (EVs), show promise for personalized medicine, offering early detection, monitoring relapse, and molecular profiling. However, challenges remain in tumor representation and methodological standards. The review discusses recent advances in glioblastoma management, including molecular pathogenesis, prognostic biomarkers, and the potential of liquid biopsies, highlighting the need for further research to improve patient outcomes.Glioblastoma, the most aggressive and common primary brain tumor, is characterized by infiltrative growth, abundant vascularization, and poor prognosis with a median survival of approximately 15 months. Despite technological advancements and improved understanding of its pathophysiology, significant progress has not been made in therapies or survival outcomes. Recent molecular profiling has led to a more refined classification of glioblastoma, identifying several genetic and epigenetic alterations, such as mutations in RTK/RAS/PI3K signaling pathways, p53, and RB, as well as IDH mutation, MGMT methylation, and 1p/19q codeletion. MicroRNAs like miR-10b and miR-21 have also been identified as prognostic biomarkers. Current treatment options include surgery, radiotherapy, and alkylating agent chemotherapy, with MGMT promoter methylation predicting benefit from temozolomide treatment. Targeted therapies based on intrinsic signaling pathways and antigenic profiles are under investigation. Liquid biopsies, including circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and extracellular vesicles (EVs), show promise for personalized medicine, offering early detection, monitoring relapse, and molecular profiling. However, challenges remain in tumor representation and methodological standards. The review discusses recent advances in glioblastoma management, including molecular pathogenesis, prognostic biomarkers, and the potential of liquid biopsies, highlighting the need for further research to improve patient outcomes.