Glioblastoma remains one of the most aggressive and treatment-resistant brain tumors, with current standard-of-care therapies offering limited survival benefits. Immunotherapy has emerged as a promising avenue to enhance anti-tumor immunity, with chimeric antigen receptor T (CAR-T) cell therapy gaining significant attention. While CAR-T therapies have demonstrated remarkable success in hematologic malignancies, their application in glioblastoma faces several challenges, including tumor heterogeneity, an immunosuppressive tumor microenvironment, limited blood-brain barrier penetration, T-cell exhaustion, and potential neurotoxicity. This review explores recent advancements in CAR-T therapy for glioblastoma, focusing on key tumor-associated antigens and innovative strategies to overcome treatment barriers. These include multi-antigen targeting, checkpoint inhibition, locoregional CAR-T delivery, synNotch, personalized CAR-T systems, and combination approaches with oncolytic viruses. We also discuss future directions for optimizing efficacy and safety. As the field advances, integrating synthetic biology and personalized antigen selection may further refine CAR-T therapy, offering renewed hope for glioblastoma patients.