High-grade gliomas (HGGs) are a challenging group of brain tumors. Identification of targetable genetic alterations such as TRK fusions are providing new treatment options. We discuss an infant who presented with hydrocephalus and a cystic mass at birth, while a solid tumor component of the mass was only appreciated later. Tumor analysis was consistent with HGG containing a TRK fusion. Despite treatment with conventional chemotherapy, his tumor progressed in size. He was started on larotrectinib and experienced a significant decrease in tumor burden. This case demonstrates that targeted therapy may be effective for a subset of TRK fusion-positive CNS tumors.