Prognosis of childhood acute myeloid leukemia (AML) has improved significantly over the past decades, from nearly no child surviving to a present probability of cure of approximately 60%. However, this can only be achieved using very intensive chemotherapy which results in relatively high rates of treatment related deaths and significant late effects. This review summarizes current and future classification of pediatric AML, ongoing phase III studies, and subgroup-directed treatment. In addition, the possibilities for more precise risk-group stratification which would allow more tailored and further refined subgroup-directed treatment are discussed. These include minimal residual disease monitoring, pharmacogenomics and the detection of AML-specific molecular abnormalities. Finally, we discuss the opportunities for innovative therapy in pediatric AML, such as the use of novel analogues, monoclonal antibody-mediated drugs, and receptor tyrosine kinase inhibitors. Given the enormous increase in our understanding of the underlying biology of AML, and the development of many new targeted drugs, it should be possible to achieve high-quality cure in nearly all children and adolescents with AML within the next few decades.