High-grade gliomas remain relatively resistant to current therapy. Local recurrence is a common feature and the majority of patients progress despite conventional therapy. One modality-gene therapy-has shown a lot of promise in early preclinical and clinical studies aimed at advancing the treatment of this disease. In this review, we provide a comprehensive overview of clinical trials involving gene therapy in the field of neuro-oncology. The use of different delivery vehicles, including liposomes, cells, and viruses, as well genes, especially cytokines and suicide genes, are explored in detail. The unique features and advantages/disadvantages of the different vectors employed are compared based on results of human studies. We discuss both the limitations and successes encountered in these clinical trials, with an emphasis on the lessons learned and potential ways of improving current gene therapy protocols.