There are several types of primary tumors of the central nervous system (CNS), and almost half of them are gliomas. In particular, glioblastoma multiforme (GBM) is very aggressive and infiltrates into the CNS parenchyma. Despite intense clinical efforts, the prognosis of patients with this type of tumors remains very poor, and has not improved in decades, with a median survival of approximately one year after diagnosis. Current treatments include surgical resection, radiotherapy and chemotherapy. However, our knowledge regarding the genetic basis, as well as the molecular signaling pathways involved in the origin and progression of the tumors has increased significantly in the last few years, thus allowing the generation of new chemotherapeutic agents that are used together with sophisticated surgical and radiation techniques. Nevertheless, new approaches are necessary to develop effective treatments for these tumors. One of these novel strategies is gene therapy which is particularly well suited to treat gliomas. In this review we will discuss current therapeutic approaches, as well as critically analyzing gene therapy methods, the use of diverse viral and non-viral vectors, different genes and strategies to treat gliomas, from experimental models to clinical applications.