Circulating liquid biopsy biomarkers in glioblastoma (GBM) offer a promising alternative to traditional tissue biopsies for diagnosis and monitoring. GBM, the most aggressive central nervous system (CNS) tumor, remains challenging to treat due to its rapid progression and poor prognosis. Current diagnostic methods, such as MRI and CT scans, and tissue biopsies, have limitations in detecting tumor progression and monitoring treatment responses. Liquid biopsy, particularly through blood and cerebrospinal fluid (CSF), provides a minimally invasive means to detect circulating biomarkers, including cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), microRNAs (miRNAs), circulating tumor cells (CTCs), extracellular vesicles (EVs), and proteins. These biomarkers can cross the blood-brain barrier (BBB), enabling real-time monitoring of GBM's genetic, epigenetic, transcriptomic, proteomic, and metabolomic changes. However, challenges such as lack of standardized methodologies and small cohort sizes limit their clinical utility. Despite these challenges, combining diverse biomarker types may enhance diagnostic accuracy and treatment monitoring. Recent studies highlight the potential of ctDNA and miRNAs as biomarkers for GBM, with ctDNA showing high specificity to the tumor but facing challenges in detection due to low concentrations and short half-life. miRNAs, which regulate gene expression, are also promising biomarkers, with specific miRNAs showing high sensitivity and specificity in distinguishing GBM from other brain pathologies. While liquid biopsy techniques are still evolving, they offer a valuable tool for improving GBM diagnosis, prognosis, and treatment monitoring.Circulating liquid biopsy biomarkers in glioblastoma (GBM) offer a promising alternative to traditional tissue biopsies for diagnosis and monitoring. GBM, the most aggressive central nervous system (CNS) tumor, remains challenging to treat due to its rapid progression and poor prognosis. Current diagnostic methods, such as MRI and CT scans, and tissue biopsies, have limitations in detecting tumor progression and monitoring treatment responses. Liquid biopsy, particularly through blood and cerebrospinal fluid (CSF), provides a minimally invasive means to detect circulating biomarkers, including cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), microRNAs (miRNAs), circulating tumor cells (CTCs), extracellular vesicles (EVs), and proteins. These biomarkers can cross the blood-brain barrier (BBB), enabling real-time monitoring of GBM's genetic, epigenetic, transcriptomic, proteomic, and metabolomic changes. However, challenges such as lack of standardized methodologies and small cohort sizes limit their clinical utility. Despite these challenges, combining diverse biomarker types may enhance diagnostic accuracy and treatment monitoring. Recent studies highlight the potential of ctDNA and miRNAs as biomarkers for GBM, with ctDNA showing high specificity to the tumor but facing challenges in detection due to low concentrations and short half-life. miRNAs, which regulate gene expression, are also promising biomarkers, with specific miRNAs showing high sensitivity and specificity in distinguishing GBM from other brain pathologies. While liquid biopsy techniques are still evolving, they offer a valuable tool for improving GBM diagnosis, prognosis, and treatment monitoring.