Human glioblastoma (GBM) is the most lethal type of brain tumor. Current therapies struggle to effectively target the tumor, leading to high recurrence rates and poor survival outcomes. Chimeric antigen receptor T-cell (CAR-T) therapy, although new and evolving, has shown success in hematological malignancies such as leukemia and lymphoma, and is currently being adapted for GBM. This review discusses emerging clinical and preclinical studies that serve as evidence for both the advancements and limitations of CAR-T therapy for GBM treatment. While prior reviews have addressed individual aspects of CAR‑T therapy for GBM, this review explores how antigen selection, delivery strategy, and the tumor microenvironment collectively influence therapeutic outcomes. Tumor antigens have been used as therapeutic targets, each exhibiting differential expression patterns and distinct anti‑tumor activity. Next‑generation multivalent CAR‑T constructs, which simultaneously engage multiple antigens or pathways, have shown promise in addressing GBM’s heterogeneity and treatment resistance. Beyond antigen targets, delivery methods have also been found to play a crucial role in determining the success of this treatment. Cerebrospinal fluid and locoregional delivery show superior tumor penetration compared to typical intravenous delivery. Still, successful CAR-T engraftment faces major challenges, such as the immunosuppressive nature of the GBM microenvironment, the transient effects of CAR-T cells, and antigen loss. It is important to note that many findings discussed in this review are derived from small-scale Phase I clinical trials, which may limit the generalizability of the conclusions. Collectively, evidence indicates that CAR-T immunotherapy represents a promising, yet evolving, treatment with the potential to improve outcomes for patients with this malignant disease.