Introduction: Although the prognosis of pediatric acute myeloid leukemia (pAML) has improved, with current survival rates up to 75%, relapse rates remain high. Areas covered: The low number of patients, the heterogeneous genomic landscape of AML, novel diagnostic techniques, divergent available treatment protocols, and dose-limiting toxicity of conventional agents all contribute to the complexity of AML treatment. This review gives an overview of the current clinical challenges with respect to diagnostics, treatment, and supportive care in pAML. Expert commentary: Due to intensified treatment regimens and improved supportive care measures, the outcome for pAML patients has improved substantially over the past years. However, most treatment protocols still rely on conventional chemotherapeutic agents with significant toxicity. Although targeted therapies promise to reduce the need for high doses of conventional agents with a subsequent decrease in toxicity, the effectiveness of these strategies remains unsatisfactory today. International collaborations are needed in order to address the ongoing therapeutic challenges of reducing toxicity while increasing effectivity. Consensus on risk-group classification, a common chemotherapy backbone and evidence-based supportive care guidelines are necessary in this context, at the same time enabling intergroup studies on new agents in subgroups.