Glioblastoma multiforme represents the most common primary malignant tumor of the adult CNS. Unfortunately, the median survival after surgical intervention alone is less than 6 months and the addition of radiotherapy can extend this time to only 9 months. Consequently, efforts aimed at developing new therapies have focused on new treatment strategies that specifically target tumor cells and spare normal cells. One such modality, gene therapy, has shown promise in the spectrum of agents utilized against brain tumors. This review highlights the principles of gene therapy and discusses the results of recent clinical trials in which gene therapy has been employed against malignant brain tumors.