Ependymal tumors across age groups are currently classified and graded solely by histopathology. It is, however, commonly accepted that this classification scheme has limited clinical utility based on its lack of reproducibility in predicting patients’ outcome. We aimed at establishing a uniform molecular classification using DNA methylation profiling. Nine molecular subgroups were identified in a large cohort of 500 tumors, 3 in each anatomical compartment of the CNS, spine, posterior fossa, supratentorial. Two supratentorial subgroups are characterized by prototypic fusion genes involving RELA and YAP1, respectively. Regarding clinical associations, the molecular classification proposed herein outperforms the current histopathological classification and thus might serve as a basis for the next World Health Organization classification of CNS tumors. Display omitted •DNA methylation profiling of ependymomas identifies nine molecular subgroups•YAP1 and RELA fusions characterize two distinct groups of supratentorial ependymoma•Patients with PFA or supratentorial RELA-positive ependymoma show dismal prognosis•Risk stratification by molecular subgrouping is superior to histological grading Pajtler et al. classify 500 ependymal tumors using DNA methylation profiling into nine molecular subgroups. This molecular classification outperforms the current histopathological grading in the risk stratification of patients.