During the past 3 decades, chemotherapeutic agents for the treatment of pediatric brain tumors have been extensively evaluated in a myriad of schedules, doses, and combinations. Remarkable advances in outcome have been achieved for certain children, notably those with medulloblastoma, but with a high cost to quality of life. In addition, the success achieved for medulloblastoma is offset by lack of progress for high-grade glioma. Despite intensive investigation, no single chemotherapeutic regimen stands out for children with high-grade glioma, with most succumbing to their disease. Further treatment intensification using conventional nonspecific chemotherapy is more likely to result in additional toxicity without major advances in survival. Genome-wide analysis using microarray technology has contributed significantly to our understanding of tumor biology, shifting the focus onto novel agents that target molecular changes crucial for tumor proliferation or survival. These selective agents are likely to be less toxic to normal cells and more effective.