Established treatments such as surgery, radiation and chemotherapy have not altered the median survival of glioblastoma, the most common malignant brain tumor. Since these failures reflect the highly invasive nature of glioblastoma, as well as the fact that few cells are actively replicating at any given point in time, therapies need to act in areas of the brain distant from the site of tumor origin and for long after their introduction. Over the past decade, laboratory studies and early clinical trials have raised hope that these therapeutic requirements may be fulfilled by gene therapy using non-replicating transgene-bearing viruses, oncolytic viruses or migratory stem cells to deliver tumoricidal transgenes. The principles behind these approaches and their initial results are reviewed.