Malignant brain tumors, including high-grade gliomas, are among the most lethal of all cancers. Despite considerable advances, including multi-modality treatments with surgery, radiotherapy, and chemotherapy, the overall prognosis for patients with this disease remains dismal. Currently available treatments necessitate the development of more effective tumor-selective therapies. The use of gene therapy for brain tumor therapy is promising as it can be delivered in situ and selectively targets brain tumor cells while sparing the adjacent normal brain tissue. In this article, we summarize the laboratory and clinical work using viral, cell-based, and synthetic vectors, as well as other strategies focused on potentiate gene delivery. Although tangible results on patients' survival remains to be further documented, significant advances in therapeutic gene transfer strategies have been made. The enthusiasm of this progress needs to be tempered by the realistic assessment of the challenges needed to be overcome. Finally, as the field of gene delivery progresses, advances must be made in identifying genes and proteins key to the treatment of malignant gliomas. Due to the great heterogeneity of malignant glioma cells, only approaches combining different strategies may be ultimately successful in defeating this disease.