Medulloblastoma and glioblastoma are the two common malignant tumors originating in the central nervous system. In addition, brain metastases occur in approximately 30% of patients with systemic malignancies. Despite significant progress in development of treatments for these tumors, the mortality rate is still high. Moreover, patients often suffer from severe long-term side effects from the aggressive treatment. Our research seeks to elucidate genetic/epigenetic mechanisms underlying brain tumor initiation and progression by using animal models, genomic sequencing as well as high-throughput drug screening, with the aim of translating the findings into improved approaches for the treatment of these devastating diseases.