Central nervous system (CNS) tumors are the most common solid tumors in children, and the leading cause of cancer-related death. Over the past decade, molecular profiling has been incorporated into treatment for pediatric CNS tumors, allowing for a more personalized approach to therapy. Through the identification of tumor-specific changes, it is now possible to diagnose, assign a prognostic subgroup, and develop targeted chemotherapeutic treatment plans for many cancer types. The successful incorporation of informative liquid biopsies, where the liquid biome is interrogated for tumor-associated molecular clues, has the potential to greatly complement the precision-based approach to treatment, and ultimately, to improve clinical outcomes for children with CNS tumors. In this article, the current application of liquid biopsy in cancer therapy will be reviewed, as will its potential for the diagnosis and therapeutic monitoring of pediatric CNS tumors.