Advances in genomic, transcriptomic and epigenomic profiling now identifies pediatric ependymoma as a defined biological entity. Molecular interrogation has segregated these tumors into distinct biological subtypes based on anatomical location, age and clinical outcome, which now defines the need to tailor therapy even for histologically similar tumors. These findings now provide reasons for a paradigm shift in therapy, which should profile future clinical trials focused on targeted therapeutic strategies and risk-based treatment. The need to diagnose and differentiate the aggressive variants, which include the posterior fossa group A and the supratentorial RELA fusion subtypes, is imperative to escalate therapy and improve survival.