Targeted Glioma Therapy—Clinical Trials and Future Directions Glioblastoma multiforme (GBM) is the most common type of glioma, with a median survival of 14.6 months post-diagnosis. Understanding the molecular profile of GBM has enabled the development of targeted therapies, particularly tyrosine kinase receptor inhibitors and immune checkpoint inhibitors. Targeted therapies work by specifically binding to GBM-specific or overexpressed markers on tumor cells, delivering cytotoxic agents to produce an antiproliferative effect. This review summarizes available information on targeted therapies used in GBM clinical trials, current obstacles and advances in targeted therapy, efficacy endpoints for investigational drugs, and promising strategies to improve drug efficacy in GBM. Gliomas include astrocytoma, oligodendroglioma, ependymoma, and other rare histologies. GBM accounts for 14.3% of all primary brain tumors and has a poor prognosis, with a 5-year survival rate of 6.8%. Despite conventional treatments, GBM relapses frequently. Genomic and transcriptomic analyses have classified GBM into subtypes, but these classifications have not significantly improved treatment outcomes for chemotherapy patients. The blood-brain barrier (BBB) poses a major challenge for drug delivery to the brain. It restricts the passage of many molecules, making it difficult for chemotherapy agents to reach their targets. However, some drugs can cross the BBB through receptor-mediated transcytosis or passive diffusion. The BBB also limits the effectiveness of many drugs, leading to systemic toxicity and reduced therapeutic efficacy. Passive targeting, which exploits the abnormal vasculature of tumors, allows drugs to reach the tumor site more easily. However, off-target effects and reduced antitumor efficacy remain challenges. Mechanical targeting involves local delivery of drugs directly to the tumor site, reducing systemic toxicity and increasing therapeutic efficacy. Active targeting uses ligands to specifically recognize tumor markers, improving drug delivery to the tumor site. Drug delivery systems for active targeting include recognition moieties, linkers, and payloads. Recognition moieties are molecules that specifically target tumor cells, while linkers connect the recognition moiety to the cytotoxic payload. Payloads are cytotoxic agents that kill tumor cells upon delivery. Targeted therapies for GBM include monoclonal antibodies, peptides, small molecules, and aptamers. These therapies aim to inhibit receptor tyrosine kinases (RTKs), which are overexpressed in GBM. RTKs are critical for cell growth and proliferation, and their inhibition can slow tumor progression. Clinical trials for GBM have tested various targeted therapies, including EGFR and PDGFR inhibitors. While some trials have shown promising results, many have not led to significant improvements in survival. The development of more effective targeted therapies remains a major challenge in GBM treatment.Targeted Glioma Therapy—Clinical Trials and Future Directions Glioblastoma multiforme (GBM) is the most common type of glioma, with a median survival of 14.6 months post-diagnosis. Understanding the molecular profile of GBM has enabled the development of targeted therapies, particularly tyrosine kinase receptor inhibitors and immune checkpoint inhibitors. Targeted therapies work by specifically binding to GBM-specific or overexpressed markers on tumor cells, delivering cytotoxic agents to produce an antiproliferative effect. This review summarizes available information on targeted therapies used in GBM clinical trials, current obstacles and advances in targeted therapy, efficacy endpoints for investigational drugs, and promising strategies to improve drug efficacy in GBM. Gliomas include astrocytoma, oligodendroglioma, ependymoma, and other rare histologies. GBM accounts for 14.3% of all primary brain tumors and has a poor prognosis, with a 5-year survival rate of 6.8%. Despite conventional treatments, GBM relapses frequently. Genomic and transcriptomic analyses have classified GBM into subtypes, but these classifications have not significantly improved treatment outcomes for chemotherapy patients. The blood-brain barrier (BBB) poses a major challenge for drug delivery to the brain. It restricts the passage of many molecules, making it difficult for chemotherapy agents to reach their targets. However, some drugs can cross the BBB through receptor-mediated transcytosis or passive diffusion. The BBB also limits the effectiveness of many drugs, leading to systemic toxicity and reduced therapeutic efficacy. Passive targeting, which exploits the abnormal vasculature of tumors, allows drugs to reach the tumor site more easily. However, off-target effects and reduced antitumor efficacy remain challenges. Mechanical targeting involves local delivery of drugs directly to the tumor site, reducing systemic toxicity and increasing therapeutic efficacy. Active targeting uses ligands to specifically recognize tumor markers, improving drug delivery to the tumor site. Drug delivery systems for active targeting include recognition moieties, linkers, and payloads. Recognition moieties are molecules that specifically target tumor cells, while linkers connect the recognition moiety to the cytotoxic payload. Payloads are cytotoxic agents that kill tumor cells upon delivery. Targeted therapies for GBM include monoclonal antibodies, peptides, small molecules, and aptamers. These therapies aim to inhibit receptor tyrosine kinases (RTKs), which are overexpressed in GBM. RTKs are critical for cell growth and proliferation, and their inhibition can slow tumor progression. Clinical trials for GBM have tested various targeted therapies, including EGFR and PDGFR inhibitors. While some trials have shown promising results, many have not led to significant improvements in survival. The development of more effective targeted therapies remains a major challenge in GBM treatment.