Glioblastoma multiforme (GBM) remains one of the most aggressive and treatment-resistant human cancers, characterized by highly infiltrative growth, extensive cellular heterogeneity, and a profoundly immunosuppressive microenvironment. Although CAR-T cell therapy has revolutionized the treatment of hematologic malignancies, its clinical impact in GBM has been limited by antigenic escape, poor tumor infiltration, T-cell exhaustion, and significant toxicity risks. Recent advances in CRISPR-Cas9 genome editing offer unprecedented opportunities to overcome these barriers by enabling precise, multiplex genetic reprogramming of T cells. In this review, we synthesize current progress in CRISPR-enhanced CAR-T engineering for GBM, focusing on strategies to overcome immune checkpoint suppression, optimize metabolic fitness, enhance trafficking across the blood–brain barrier, reduce neuroinflammation-associated toxicities, and generate universal allogeneic CAR-T products. We also compare the genomic target spaces of candidate guide RNAs (crRNA, d10r10, X37) and highlight their predicted off-target profiles relevant to GBM therapeutic design. Preclinical studies demonstrate that CRISPR-edited CAR-T cells targeting EGFRvIII, IL-13Rα2, HER2, and B7-H3 significantly enhance survival in murine GBM models, while emerging clinical trials indicate acceptable safety and early evidence of anti-tumor activity. We further discuss technological innovations—including base editing, prime editing, CRISPRi/a, non-viral delivery platforms, and precision-medicine–guided CAR design—as well as regulatory, ethical, and manufacturing considerations required for clinical translation. Collectively, these advances underscore the transformative potential of CRISPR-engineered CAR-T therapies to reshape GBM treatment and pave the way toward more effective and accessible cellular immunotherapies. Keywords. Glioblastoma multiforme (GBM), CAR-T cell therapy, CRISPR-Cas9 genome editing, T-cell engineering, Immune checkpoint resistance, Tumor microenvironment, Guide RNA design, EGFRvIII, IL-13Rα2, Universal allogeneic CAR-T cells, Preclinical models, Precision immunotherapy