Despite advances in surgical and adjuvant therapy, the prognosis for malignant gliomas remains dismal. This gloomy scenario has been recently brightened by the increasing understanding of the genetic and biological mechanisms at the basis of brain tumor development. These findings are being translated into innovative therapeutic approaches, including gene therapy, virotherapy, and vaccination, some of which have already been experimented in clinical trials. The advantages and disadvantages of all these different therapeutic modalities for malignant gliomas will be critically discussed, providing perspective for future investigations.