BACKGROUND: Brain is the very organ where functional preservation is critical, however, neoadjuvant chemotherapy (NAC) has not yet been systematically applied into the treatment of glial tumors. METHODS: Since February 2006, treatment for gliomas at Keio University Hospital has been tailored by molecular guidance: grade II-III gliomas with 1p19q codeletion or MGMT methylation have been treated by upfront chemotherapy, and the second surgery was planned after tumor volume reduction by NAC in the cases in which initial surgery was incomplete. The study includes the consecutive patients who fulfilled the following criteria: a) histopathological diagnosis of diffuse glioma of WHO grade II or III; b) no or scant contrast-enhancement; c) 1p19q codeletion or promoter methylation of the MGMT gene; d) written informed consent. RESULTS: Twenty gliomas (grade II: 17, grade III: 3) suggested to be responsive to chemotherapy have been treated by the neoadjuvant strategy. Curiously, the majority of gliomas referred to our hospital invaded into the eloquent areas, and the particular patient cohort provided the unique opportunity to see the true chemotherapeutic response. CR/PR/MR was in 9/18 evaluable cases, and there was no PD within 6 months. Importantly, the second-look removal after tumor volume reduction was performed in 12/17 incompletely resected tumors. CONCLUSIONS: NAC according to molecular guidance could often produce significant volume reduction of the incompletely resected gliomas. For chemosensitive low-grade gliomas, the upfront chemotherapy might hold optional advantages over upfront radiotherapy: radiotherapy can be saved for later malignant transformation; tumor volume reduction by NAC could provide the chance of radical resection that is not initially possible. SECONDARY CATEGORY: Neuropathology & Tumor Biomarkers.