Nucleic acid based therapeutics offer the possibility of tailor-made treatment of malignant diseases. For recurrent glioblastoma multiforme (GBM), the most aggressive type of brain tumor, no accepted treatment exists, making therapeutically active nucleic acids a viable option. In this review, current preclinical and clinical studies harnessing the potential of antitumoral nucleic acids for GBM treatment will be considered. These include gene therapy to over-express antitumoral gene products, RNA interference to knock down components that promote tumor progression, and the tumor-targeted delivery of antitumoral double stranded RNA. Vectors applied in GBM for the delivery of nucleic acids will be discussed. These include non-replicating and replicating (oncolytic) viruses, as well as non-viral delivery vectors based on polycations or cationic lipids.