Pediatric malignant brain tumors represent the most frequent cause of cancer-related deaths in childhood. The triad of the therapeutic scheme of surgery, radiotherapy and chemotherapy has improved patient management, but with minimal improvement in patients’ prognosis. Emerging molecular targets and mechanisms have pointed out novel approaches and schemes for pediatric brain tumor therapy, enabling personalized medical treatment. Advances in the field of epigenetics and their interplay with genetic changes have enriched our knowledge of the molecular heterogeneity of these neoplasms and have revealed important genes that affect crucial signaling pathways involved in tumor progression. The great potential of epigenetic therapy lies mainly in the widespread location and the reversibility of epigenetic alterations, proposing a wide range of targeting options, including the possible combination with chemo- and immunotherapy, significantly increasing their efficacy. Epigenetic drugs, including inhibitors of DNA methyltransferases, histone deacetylases and demethylases, are currently being tested in clinical trials on pediatric brain tumors. Additional novel epigenetic drugs include protein and enzyme inhibitors that modulate epigenetic modification pathways, such as Bromodomain and Extraterminal (BET) proteins, Cyclin-Dependent Kinase 9 (CDK9), AXL, Facilitates Chromatin Transcription (FACT), BMI1, and CREB Binding Protein (CBP) inhibitors, which can be used either as standalone or in combination with current treatment approaches. In this review, we discuss recent progress on epigenetic drugs that could be possibly used against the most common malignant tumors of childhood, such as medulloblastomas, high- grade gliomas and ependymomas.