Pediatric brain tumors are a leading cause of cancer-related death in children. In recent years, the application of next-generation sequencing and other high-throughput technologies to analysis of pediatric brain tumors has generated an abundance of molecular information. This has provided an unprecedented understanding of their biology and is refining tumor classification into clinically relevant subgroups. In this review, we provide an overview of our evolving molecular knowledge of the commonest pediatric brain tumors, pilocytic astrocytomas, ependymomas, medulloblastomas, and pediatric glioblastomas, as well as the biological and potential clinical implications of this new knowledge. Studies aimed at investigating intratumoral heterogeneity are also discussed.