Gene therapy approaches for malignant brain tumors evolved from the need to develop new treatment modalities, increasing insights in the molecular basis of tumorigenesis and the advent of recombinant DNA technology. Immunotherapy of tumors growing in an immunologically privileged organ is a challeng ing task for researchers and clinicians. Both strategies, systemic immunization and local overexpression of cytokines in the brain tumor, have been successfully applied to experimental tumor models. The first clinical gene immunotherapy trials of malignant gliomas uses a vaccine consisting of tumor cells and fibro-blasts genetically modified to express interleukin-2. Chemotherapy of brain tumors is based on the conversion of relatively nontoxic prodrugs into cytotoxic chemotherapeutic agents by suicide genes. Cytosine deaminase from E. coli and thymidine kinase from herpes simplex virus confer lethal cytotoxicity to cells expressing either one of the suicide genes in the presence of the appropriate prodrug 5-fluorocytosine or ganciclovir. Several gene therapy trials have been approved for the treatment of malignant brain tumors with herpes simplex thymidine kinase and ganciclovir. Insights in the molecular basis of tumorigenesis stimulated therapy approaches for restoration of cell cycle gene functions and growth control in malignant tumor cells. Introduction of wild-type p53 tumor suppressor gene into tumor cells lacking the normal protein has not only been shown to revert the malignant phenotype, but also to induce apoptosis in response to DNA damaging by conventional chemotherapy and radiotherapy treatment. These findings are now being translated into clinical gene transfer trials.