The optimal treatment strategy for anaplastic oligodendroglial (AO) tumors is evolving. Molecular profiling of oligodendrogliomas have shown distinctive genetic patterns characterized by combined deletions of chromosome arms 1p and 19q, O(6)-methylguanine methyltransferase (MGMT) methylation, and isocitrate dehydrogenase 1 (IDH1) mutations; they are all prognostic factors for patients with AO. In addition, a strong association has also been found between the CpG island hypermethylation phenotype (CIMP) status and MGMT promoter methylation. Long term follow up data of the Radiation Therapy Oncology Group (RTOG) 9402 and the European Organisation for Research and Treatment of Cancer (EORTC) 26951 studies demonstrate clear evidence that for patients with codeleted 1p19q AO, early chemotherapy with radiation offers a significant improvement in overall survival compared with early radiation, even with salvage chemotherapy at tumor relapse, and thus establishes the 1p19q allelic loss as a predictive marker distinct from tumors without the chromosome change. Radiotherapy alone is no longer considered an adequate treatment for this patient population. In cases with no 1p19q deletion, most neuro-oncologists recommend incorporating radiotherapy into the upfront treatment strategy. However, there are still unanswered questions regarding whether upfront chemotherapy, omitting/deferring radiotherapy, in the desire to avoid late neurocognitive toxicity of radiotherapy should be the initial therapy for AO tumors with codeleted 1p19q, or whether temozolomide, an oral agent with a better toxicity profile, can be substituted for procarbazine, lomustine, and vincristine (PCV). Further studies are warranted and the increasing understanding of molecular pathways involved may lead to more selective therapeutic targets in the future.