Therapeutic strategies utilized in recently completed Phase III clinical trials in children with de novo acute myeloid leukemia have led to long-term disease-free survival in 50 - 60% of children. This review describes the contributions from early intensification of therapy and postremission intensification using highly myelosuppressive chemotherapy strategies and discusses the controversial roles of allogeneic bone marrow transplantation, maintenance therapy and CNS irradiation. Current strategies focusing on the identification of critical biologic features and measurements of early response to therapy allow for greatly improved risk group stratification. Future improvements in the treatment of children with acute myeloid leukemia will depend on a better understanding of the biology of the disease, targeted therapeutic approaches directed to specific biologic targets, selective use of allogeneic transplantation and innovative clinical trial designs that will allow for the testing of an increasing number of new agents in increasingly small numbers of patients in defined risk groups.