Down syndrome (DS) is the most common chromosomal abnormality in live newborn children and results from acquisition of either an intact extra copy of chromosome 21 or a portion of it, the so-called DS critical region. Multiple benign hematologic abnormalities are common in newborns with DS and undergo spontaneous resolution within the first month of life. Transient abnormal myelopoiesis (TAM), an unusual myeloproliferative condition restricted to DS, is present at birth in a minority of infants with DS. Although usually clinically indolent and spontaneously remitting, TAM may be associated with significant morbidity secondary to hepatic fibrosis. In a subset of cases, TAM either progresses to or recurs as myeloid leukemia of DS (ML-DS) during the first three years of life, typically with morphologic and immunophenotypic evidence of megakaryocytic differentiation. Older children with DS are also at increased risk for development of acute leukemia, usually B-lymphoblastic leukemia (B-ALL). In this chapter, the benign hematologic abnormalities of DS are discussed. In addition, the clinical, laboratory, and pathologic findings in TAM and the pathogenetically related AMKL of DS are discussed in detail with an emphasis on their differential diagnosis. Finally, the pathogenetic and pathologic features of B-ALL of DS are discussed.