Glioblastoma multiforme (GBM) is the most common type of glioma, with a median survival of 14.6 months post-diagnosis. The development of specific targeted therapies, such as tyrosine kinase receptor inhibitors and immune checkpoint inhibitors, has been crucial in improving treatment outcomes. Targeted therapeutics are drugs that bind to specific markers on the tumor surface, containing a recognition moiety linked to a cytotoxic agent to produce an antiproliferative effect. This review summarizes the available information on targeted therapeutics used in clinical trials for GBM, outlines current obstacles and advances in targeted therapy, and discusses strategies to enhance drug efficacy. Gliomas account for nearly 25% of all primary brain tumors and are classified into low-grade (LGG) and high-grade (HGG) gliomas. GBM, the most aggressive form, has a poor prognosis with a 5-year survival rate of 6.8%. Despite standard treatments including maximal tumor resection, radiotherapy, and temozolomide (TMZ), relapse and progression are common. Advances in genomics and transcriptomics have led to the classification of GBMs into subtypes based on genetic expression profiles, which have guided targeted therapy development. The blood-brain barrier (BBB) poses significant challenges for drug delivery, as it restricts the passage of most molecules. Strategies to overcome this barrier include passive targeting, mechanical targeting, and active targeting. Passive targeting leverages the Enhanced Permeation and Retention (EPR) effect, while mechanical targeting involves local application of drugs to the tumor site. Active targeting uses ligands to recognize tumor-specific biomarkers, such as receptor tyrosine kinases (RTKs) and immune checkpoint inhibitors. Targeted therapies for GBM often target RTKs, including EGFR, PDGFR, VEGFR, MET, and FGFR. Monoclonal antibodies, peptides, small molecules, and aptamers are used as recognition moieties. Linkers connect the recognition moiety to the cytotoxic payload, which can be conventional chemotherapeutics or novel agents. Clinical trials for targeted therapies have shown mixed results, with some demonstrating promising cytotoxic effects but others failing to improve survival rates. The review also discusses the challenges and future directions in targeted therapy for GBM, emphasizing the need for better drug delivery systems and the development of more effective treatments to improve patient outcomes.Glioblastoma multiforme (GBM) is the most common type of glioma, with a median survival of 14.6 months post-diagnosis. The development of specific targeted therapies, such as tyrosine kinase receptor inhibitors and immune checkpoint inhibitors, has been crucial in improving treatment outcomes. Targeted therapeutics are drugs that bind to specific markers on the tumor surface, containing a recognition moiety linked to a cytotoxic agent to produce an antiproliferative effect. This review summarizes the available information on targeted therapeutics used in clinical trials for GBM, outlines current obstacles and advances in targeted therapy, and discusses strategies to enhance drug efficacy. Gliomas account for nearly 25% of all primary brain tumors and are classified into low-grade (LGG) and high-grade (HGG) gliomas. GBM, the most aggressive form, has a poor prognosis with a 5-year survival rate of 6.8%. Despite standard treatments including maximal tumor resection, radiotherapy, and temozolomide (TMZ), relapse and progression are common. Advances in genomics and transcriptomics have led to the classification of GBMs into subtypes based on genetic expression profiles, which have guided targeted therapy development. The blood-brain barrier (BBB) poses significant challenges for drug delivery, as it restricts the passage of most molecules. Strategies to overcome this barrier include passive targeting, mechanical targeting, and active targeting. Passive targeting leverages the Enhanced Permeation and Retention (EPR) effect, while mechanical targeting involves local application of drugs to the tumor site. Active targeting uses ligands to recognize tumor-specific biomarkers, such as receptor tyrosine kinases (RTKs) and immune checkpoint inhibitors. Targeted therapies for GBM often target RTKs, including EGFR, PDGFR, VEGFR, MET, and FGFR. Monoclonal antibodies, peptides, small molecules, and aptamers are used as recognition moieties. Linkers connect the recognition moiety to the cytotoxic payload, which can be conventional chemotherapeutics or novel agents. Clinical trials for targeted therapies have shown mixed results, with some demonstrating promising cytotoxic effects but others failing to improve survival rates. The review also discusses the challenges and future directions in targeted therapy for GBM, emphasizing the need for better drug delivery systems and the development of more effective treatments to improve patient outcomes.