Surgical resection with or without radiation therapy confers long-term remission in approximately half of the patients newly diagnosed with ependymoma. Chemotherapy has a limited role in the management of ependymoma. In newly diagnosed infants, chemotherapy is utilized as an attempt to defer radiation. The use of chemotherapy in older children has provided no conclusive benefit. The largest experience with chemotherapy in ependymoma has been in children with recurrent disease. In this section, we will analyze the principal institutional and cooperative group phase I, phase II, and phase III clinical trials utilizing single-agent and multiagent chemotherapy in patients with recurrent ependymoma. In addition, future directions relating to novel medical oncologic therapies will also be discussed.