Acute leukemias in children with Down syndrome (DS) are characterized by unique clinical and biological features. Notable among DS children with acute myeloid leukemia (AML), is the high frequency of the acute megakaryocytic leukemia (AMkL) subtype, which uniformly harbor somatic mutations in the transcription factor GATA1 gene. DS patients with AML, and in particular AMkL, have event-free survival rates of 80-100% in contrast to event-free survival rates of less than 35% for non-DS children with AMkL. DS children with acute lymphoblastic leukemia have a more heterogeneous disease, with approximately 30% of the patients having somatic JAK2 mutations, heightened methotrexate sensitivity and higher rates of treatment-related toxicities. These features highlight a striking relationship between genes localized to chromosome 21, leukemogenesis and sensitivity to leukemia chemotherapy agents.