Pediatric neoplasms represent a biologically distinct group of diseases that differ fundamentally from adult tumors in incidence, pathogenesis, and molecular drivers. Although rare, they remain the leading cause of disease-related mortality in children. Hematologic malignancies predominate, followed by central nervous system, soft tissue, and bone tumors, as well as embryonal tumors. Over the past decades, genomic, transcriptomic, and epigenetic studies have transformed the understanding of childhood cancers, revealing that many arise from single initiating events—most often chromosomal rearrangements—resulting in molecularly homogeneous entities with diagnostic and therapeutic relevance. These discoveries have driven major advances in clinical care. Molecular stratification now guides risk assessment and therapy in several malignancies, exemplified by FOXO1 fusion testing in rhabdomyosarcoma and cytogenetic and genomic profiling in neuroblastoma and Wilms tumor. The identification of characteristic kinase or transcription factor fusions has reshaped the classification of mesenchymal tumors, enabled the recognition of new entities, and provided actionable targets for an expanding number of FDA-approved targeted and immunotherapeutic agents. Parallel progress in understanding tumor predisposition syndromes has revealed germline pathogenic variants in up to 17% of pediatric patients, underscoring the importance of integrated genetic evaluation. Together, these developments mark a shift from morphology-based diagnosis toward an integrated molecular taxonomy of pediatric tumors. As large-scale multi-omic studies continue to refine the biology of these rare neoplasms, they will further enable personalized therapeutic approaches and improve outcomes for children with cancer.