Transient leukemia of Down syndrome (DS-TL), also known as transient myeloproliferative disorder of Down syndrome (DS) and transient abnormal myelopoiesis of DS, occurs in approximately 10% of DS neonates and in phenotypically normal neonates with trisomy 21 mosaicism. In DS-TL, peripheral blood analysis shows variable numbers of blasts and, usually, thrombocytopenia; other cytopenias are uncommon. Bone marrow characteristics of DS-TL are, likewise, variable, though (in contrast to other leukemias) the bone marrow blast differential can be lower than the peripheral blood blast differential. The blasts of DS-TL typically show light microscopic, ultrastructural, and flow cytometric evidence of megakaryocyte differentiation. DS-TL neonates have a approximately 15% risk of developing potentially fatal liver disease and show <10% incidence of hydrops fetalis. Additional manifestations of DS-TL include cutaneous involvement, hyperviscosity, myelofibrosis, cardiopulmonary failure, splenomegaly, and spleen necrosis. Despite its typical transient nature, 20% to 30% of DS-TL patients develop overt (nontransient) acute leukemia, usually within 3 years and typically of the M7 phenotype (acute megakaryoblastic leukemia). The pathogenesis of DS-TL (and of subsequent acute leukemia) involves mutation of GATA1 (on chromosome X), which normally encodes a transcription factor integral to normal development of erythroid, megakaryocytic, and basophilic/mast cell lines. The pathogenetic role of trisomy 21 in DS-TL is unclear. Though indications for chemotherapy in DS-TL have not been firmly established, the blasts of DS-TL are sensitive to low-dose cytosine arabinoside.