Central nervous system (CNS) cancers are the second most frequent malignancy (and the most common solid tumor) in childhood. In recent years, significant advances in surgery, radiotherapy, and chemotherapy have improved survival in children with these tumors. However, a significant proportion of patients with CNS tumors suffer progressive disease despite such treatment. Advances in the understanding of the nature of the blood-brain/tumor barrier, chemotherapy resistance, tumor biology, and the role of angiogenesis in tumor progression and metastases have led to the advent of newer therapeutic strategies that circumvent these obstacles or target specific receptors that control signal transduction and/or angiogenesis in tumor cells. Ongoing clinical trials will determine whether these novel treatment modalities will improve outcomes for children with brain tumors.