<p>Tumors of the central nervous system (CNS) are the most common pediatric tumor type and the leading cause of cancer-related death in children and adolescents. In recent decades, multiple molecular approaches have been applied to decipher the biological nature of these aggressive cancers, leading to more precise tumor classification and precision medicine approaches. Nevertheless, treatment of these tumors remains challenging due to the sensitive location, young age of patients, and resistance to current therapeutic strategies. Recently, several targeted therapy targets have been approved by the US Food and Drug Administration and European Medicines Agency for the treatment of pediatric brain tumors or are being investigated within clinical trials. Furthermore, the improved sensitivity of methods to detect small amounts of DNA or RNA in liquid biopsy samples provides a novel source for an almost limitless, less invasive, and longitudinal monitoring opportunity. Take home message: Targeted therapies have added novel therapeutic options to combat pediatric CNS tumors and liquid biopsy is promising to aid in guiding precision oncology approaches. However, single-agent therapy is rarely curative, necessitating further efforts to investigate improved therapeutic regimens including these novel therapies.</p>