Hydroxyurea has been used since the early 1970s to potentiate the effects of radiation in the treatment of primary gliomas. In the only randomized study, a statistically significant increase in time to tumor progression for glioblastoma patients was noted for those receiving hydroxyurea. In other studies, hydroxyurea has been used as a cell-cycle phase-specific agent to improve survival in patients with recurrent gliomas and, in combination with 5-fluorouracil, to increase cell kill and as a potential DNA polymerase inhibitor. Other protocols have used hydroxyurea during radiation therapy in medulloblastoma and in combination chemotherapy for metastatic brain tumors as well. While widely used in the treatment of primary and secondary brain tumors, hydroxyurea trials usually have not been randomized or otherwise controlled; most have been nonrandomized, phase II activity studies. With the conclusion of some current trials, it is conceivable that the use of hydroxyurea may be more clearly defined in the treatment of tumors affecting the nervous system.