Chronic myeloid leukemia (CML) is a relatively rare hematopoietic malignancy in the pediatric and adolescent population. This makes it difficult to perform clinic trials that can define the best therapeutic option when considering the impact of tyrosine kinase inhibitors (TKIs) versus the established approach of allogeneic hematopoietic cell transplantation (HCT). With the relatively low toxicity of TKIs, there are little data regarding when HCT or long-term TKI therapy is a better option. There are even less data regarding the duration of TKI treatment in the pediatric CML in chronic phase (CML-CP) patients who may receive over 60 years of therapy. As children and adolescent are treated for longer times with TKIs, it has become clear that toxicities may make long-term TKI therapy less attractive compared to allogeneic HCT. HCT has the long-term complications of growth failure, infertility, chronic graft-versus-host disease (GVHD), metabolic syndrome, and secondary malignancies, whereas prolonged TKIs may cause growth failure, hepatic, and cardiac complications. Moreover, HCT is a potentially curative intervention, whereas TKI is not curative, requiring prolonged exposure. In this article, we discuss the relative merit of the 2 therapeutic approaches and recommend that all children and adolescents with CML-CP should initially be treated with imatinib and maintained with TKI therapy indefinitely if there is a good response. We recommend that allogeneic HCT with an HLA-identical sibling donor or closely matched unrelated donor be considered for patients with treatment failure or recurrence after receiving salvage second-generation TKI treatment. We also conclude that randomized international trials are urgently needed to evaluate the best therapies for pediatric CML.