Myeloid leukemias in childhood Down syndrome (DS) comprise a unique disease entity. Transient Leukemia (TL) in neonates with DS is a neoplastic disorder characterized by Acute Myeloid Leukemia (AML)-like hematological abnormalities, which spontaneously resolves in several weeks or months. On the other hand, AML in young children with DS (AML-DS), which occurs several years later, usually after spontaneous remission of TL, does not resolve spontaneously and is a lethal disorder unless treated. These two types of myeloid leukemia in DS are a spectrum of disorders with common GATA1 gene mutations and a background of trisomy 21, but arise in different organs at different developmental stages. TL is thought to arise in the fetal liver and is often accompanied by hepatic fibrosis in severe cases, whereas AML-DS arises in the postnatal BM and is often accompanied by myelofibrosis, with fibrosis of both organs being caused by a common mechanism through cytokines produced by leukemic blasts. The mechanism of the spontaneous remission of TL is unclear and two major hypotheses have been proposed: 1) a transition of major hematopoietic organs from the liver to the BM after birth might stop TL blast growth (extrinsic/ environmental theory); and 2) the genetic mechanism controlling the switch from fetal- to adult-type haematopoiesis might trigger the end of TL blast growth (intrinsic/genetic theory).