The acute myeloid leukemias (AML) represent a heterogeneous group of malignancies derived from the pluripotent hematopoietic stem cell. These leukemias are generally characterized by genetic lesions that result in a combination of defects causing unregulated proliferation of cells and defects in cellular maturation (Gilliland and Griffin 2002). AML accounts for approximately 15–20% of acute leukemia in children. In contrast to acute lymphoblastic leukemia (ALL) in childhood, for which an age-related peak incidence in children is associated with unique genetics, biology, and response to therapy, AML in children is very heterogeneous with large subsets representing disease that is generally similar to that in adults. Pediatric AML does not exhibit a dramatic peak in childhood other than for infants with disease involving translocation of the mixed lineage leukemia (MLL) gene. In both children and adults, AML is a relatively drug-resistant disease. Progress in improving outcome over the past 40 years has been associated with the use of pulses of high-dose, high systemic exposure intensive chemotherapy approaches. Refinements in chemotherapy regimens and major improvements in supportive care practices have resulted in the ability to achieve complete remission (CR) in 80–90% of pediatric patients and long-term event free survival (EFS) in 40–60% of patients. While high-dose chemotherapy Consolidation with hematopoietic stem cell transplantation (HSCT) once represented the predominant treatment approach, recent studies have revealed that large subgroups of patients characterized by specific cytogenetic and molecular features do not require transplantation as initial therapy. Conversely, other molecular analyses have identified very high risk subgroups at the time of initial diagnosis that possess highly resistant stem cell disease and are likely to benefit from stem cell transplantation.