OBJECTIVEThe rationale and current evidence for usingp53gene replacement as a potential treatment for human gliomas are reviewed. The possible benefits of and obstacles to this approach are delineated.METHODSOne approach to overcoming the poor outcomes associated with conventional glioma therapies involves the replacement of tumor suppressor genes that are fundamental to glioma development. Thep53gene is one of the most frequently mutated genes in human gliomas, and loss of p53 function is critical to the development of glial neoplasms. Consequently, replacement of thep53gene using viral vectors may be a potential treatment for human gliomas.RESULTSIn vitro studies demonstrate that adenovirus-mediatedp53gene transfer into gliomas with mutantp53results in massive apoptosis. Similarly, transfer ofp53inhibits tumor growth in vivo. In contrast to mutantp53gliomas, wild-typep53glioma cells are resistant to the apoptotic effects ofp53transfer, but this resistance can be overcome by the addition of deoxyribonucleic acid-damaging agents such as ionizing radiation or chemotherapy. The main obstacle top53gene therapy involves the limitations associated with current modes of delivery.CONCLUSIONPreclinical data strongly support the use ofp53gene transfer as a potential treatment for human gliomas.