Radiotherapy has remained the mainstay of treatment for children with intrinsic, diffuse pontine tumors in spite of over 20 years of clinical trials attempting to validate the additional role of chemotherapy. Conventional phase II clinical trials conducted in patients with recurrent or progressive brainstem gliomas using single chemotherapy agents such as cyclophosphamide, carboplatin, cisplatin, etoposide and thiotepa or combinations of chemotherapy agents have produced low response rates in the range of 15-20%. Preradiotherapy chemotherapy phase II trials in newly diagnosed patients have yielded similar results with a therapeutic window as long as 4 months. Preliminary data from protocols employing high-dose chemotherapy with stem cell support have also met with disappointment. The one published phase III trial conducted by the Children's Cancer Study Group comparing radiotherapy with radiotherapy plus chemotherapy (CCNU, vincristine and prednisone) failed to establish a benefit to multimodality therapy. Current studies include the use of radiosensitizing chemotherapy (carboplatin, estramustine and cisplatin) in newly diagnosed patients and more intensive neoadjuvant chemotherapy trials. Major advances in our management await insights into molecular vulnerability of high-grade gliomas.