Diffuse gliomas constitute a diverse group of malignant brain tumors with varying aggressive course and heterogeneous survival. Although the mainstay of treatment of these distinct tumors is still based on the combination of surgery and classical therapeutic weapons such as radiotherapy and chemotherapy, important advances have been achieved over the past decades leading to meaningful improvements in survival times. In addition, recent progress in molecular profiling has allowed the identification of patients with better prognosis and more likely to respond to specific antitumor treatment. This is particularly true for grade II and III 1p/19q-codeleted gliomas, a subset of tumors in which data maturation after long-term follow-up have proved extremely important for accurate assessment of efficacy. This article aims at providing a review of the current specific antitumor treatment of diffuse glioma, particularly grade II and III glioma and glioblastoma, with special emphasis on the most relevant clinical trials conducted in these populations of patients.