Recent therapeutic advances have significantly transformed the management of selected pediatric malignancies. We conducted a narrative review of recently approved therapies with demonstrated clinical impact in pediatric oncology. Evidence from pivotal clinical trials was integrated with real-world experience at the Pediatric Cancer Center Barcelona (PCCB). Fifty-three new oncological drugs with pediatric indication were available in 2025 that were not in routine clinical practice in 2020. We reviewed 18, those available at the PCCB, to demonstrate their meaningful clinical activity, the improved disease control and favorable toxicity profiles. Overall, 688 patients have benefited from these new agents. Real-world experience supports their feasibility and clinical benefit in many pediatric cancers. We realized that a significant number of novel therapies have been approved in the last 5 years and represent an important step toward precision oncology in pediatric cancer. Their integration into clinical practice is reshaping treatment paradigms and offering real opportunities for patients with otherwise limited options. Ongoing studies will define their long-term impact, optimal sequencing, and role within multimodal treatment strategies.