PurposeChildren with Down syndrome (DS) carry an elevated risk of developing clonal hematologic disorders. In this review, we summarize reported data describing the incidence of leukemia in children with DS and associated leukemic cell phenotypic and functional features.Patients and MethodsMajor leukemic subtypes, acute lymphoblastic leukemia (ALL), acute nonlymphoblastic leukemia (ANLL), myelodysplastic syndromes (MDS), and transient abnormal myelopoiesis (TAM) are evaluated in the context of patient age and treatment responsiveness.ResultsIt is apparent that although leukemia in children with DS is a relatively frequent event, prognosis with current conventional therapeutic strategies is excellent.ConclusionsTreatment options for TAM, a monoclonal cellular proliferation in neonates, are discussed.