Although most children with cancer can be cured of their disease, a subset of patients with adverse tumor types or biological features, and those with relapsed or refractory disease have significantly worse prognosis. Furthermore, current cytotoxic therapy is associated with significant late effects. Precision oncology, using molecular therapeutics targeted against unique genetic features of the patient's tumor, offers the potential to transform the multimodal therapy for these patients. Potentiated by advances in sequencing technology and molecular therapeutic development, and accelerated by large-scale multi-institutional basket trials, the field of pediatric precision oncology has entered the mainstream. These novel therapeutics have important implications for surgical decision making, as well as pre- and postoperative care. This review summarizes the current state of precision medicine in pediatric oncology including the active North American and European precision oncology clinical trials. LEVEL OF EVIDENCE: Treatment study Level V.