Leukemia remains the most prevalent cancer in children, accounting for 25–30% of pediatric malignancies. Despite significant advancements in treatment leading to survival rates exceeding 90% for acute lymphoblastic leukemia (ALL) and 75% for acute myeloid leukemia (AML) in developed countries, challenges persist, particularly in managing refractory and relapsed cases. This review highlights the critical role of genetic profiling in the diagnosis and treatment of pediatric leukemia, emphasizing its potential to guide personalized therapeutic strategies. The integration of next-generation sequencing has revolutionized our understanding of the genetic heterogeneity of leukemia, enabling the identification of actionable mutations that inform risk stratification and targeted therapies. Furthermore, novel treatment modalities, including immunotherapy and targeted agents, are emerging as promising options for improving outcomes in high-risk patients. However, the need for less toxic treatment regimens remains urgent, as survivors often face long-term health challenges. This review underscores the importance of ongoing research to develop innovative therapies that minimize toxicity while maximizing efficacy, ultimately aiming to provide the right treatment for each patient at the right time.