<p>Pediatric tumors represent a major cause of disease-related mortality in children and exhibit biological features that differ markedly from those of adult cancers. Pediatric malignancies display unique molecular architectures, with lower mutation frequency, higher frequency of chromosomal alterations such as gene rearrangement and amplification, a distinct alteration spectrum marked by dysregulated developmental genes, as well as a characteristic pattern of differentiation blockage. These alterations often arise during developmental windows and sustain tumor dependency, providing unique drug targets for targeted therapy. This review first describes the molecular characteristics and oncogenic drivers of pediatric tumors, as well as the potential mechanisms underlying the formation of oncogenic driver events in these tumors. It subsequently systematically synthesizes recent advances in targeted therapeutic strategies for pediatric tumors, categorizing strategies by disease type and oncogenic driver events, including oncofusion-directed inhibitors, agents targeting amplified or mutated genes, differentiation-inducing approaches, antibody-based therapies, and cellular therapies. We highlight both pediatric-specific drug development and the extrapolation of adult therapies to pediatric patients, while underscoring persistent challenges in clinical translation. This work advocates for a biology-driven framework to accelerate the development of effective targeted therapies for pediatric tumors.</p>