High-grade glioma is the most frequently occurring primary brain tumor and is associated with a poor prognosis. Current treatment regimens have had only a modest effect on the progressive course despite recent advances in surgery, radiotherapy, and chemotherapy. Gene therapy for brain tumors represents a novel and promising therapeutic approach and has been investigated clinically for the last two decades. The strategies of gene therapy include suicide gene therapy, immune gene therapy, oncolytic viral therapy, tumor suppressor gene therapy, and antisense therapy. Here, we review gene therapy approaches considering the clinical results, limitations, and future directions.