Chemotherapy has become an important modality in the management of children with brain tumors. Factors that impede improved effectiveness of anti-neoplastic drugs are being identified and addressed. Specific agents have emerged that show anti-brain tumor activity alone or in combination therapy. Use of these agents requires facility regarding their dosing, routes of delivery, mechanisms of action, metabolism and toxicities. Multi-institution cooperative group trials provide the optimum means by which to evaluate the effectiveness of chemotherapy in children with brain tumors.