Malignant gliomas are attractive targets for gene therapy because of their relatively well-localized distribution. Several new strategies have been devised that target different aspects of glioma biology. Gene transfer can be used to synthesize chemotherapy drugs that block DNA synthesis within these highly mitotic tumors. New genes can be introduced that restore the functions of mutated tumor suppressor genes or block the molecular pathways needed for tumor angiogenesis. Alternatively, the immune response to these tumors can be augmented by the local production of cytokines. Finally, viruses themselves can be used as tumoricidal agents by designing viruses that selectively replicate and destroy tumor cells. The advantages and limitations of these approaches are discussed in the context of their possible application to the treatment of these highly lethal malignancies.