Astrocytomas are the most common group of childhood brain tumors. Approximately 20% of these lesions are histologically malignant tumors that often prove fatal within 2 years of diagnosis, despite the use of surgery and conventional radiotherapy. During the last 15 years, considerable attention has been focused on evaluating the potential role of chemotherapy as a means of improving survival. Although several agents have been observed to have modest therapeutic activity against these tumors, the optimal strategies for improving disease control have yet to be defined. This article will review the results that have been achieved in previous studies using a variety of single and multi-agent chemotherapeutic regimens, and also the rationale for ongoing trials of the major cooperative groups, and will discuss the challenges that are inherent in designing and interpreting therapeutic studies for these tumors. Ways in which currently available approaches may be incorporated into future therapeutic strategies will also be discussed and a brief review of the extensive array of promising new treatment approaches will be presented.