Hematopoietic stem cells (HSCs), which are responsible for producing all blood cell types, frst appear in the early stage of embryonic development and transit through several different tissues, including the yolk sac, aorta-gonadmesonephros (AGM) region, placenta, and fetal liver, before colonizing in the bone marrow where they reside throughout the individual’s life. HSCs, characterized by the ability to self-renew and generate all types of blood cells, are supported by their specifc environment called niches and depend on many developmental signaling pathways, molecules, and cytokines for their generation, maintenance, and expansion. Any disruption in this well-balanced system may cause aberrant HSC production, leading to malignant hematopoiesis. Leukemic stem cells (LSCs), originally identifed using xenograft models of acute myeloid leukemia (AML), are a distinct cell population that can initiate leukemia in immunodefcient mice. LSCs are thought to emerge from HSCs or hematopoietic progenitors after obtaining multiple genetic changes that provide aberrant growth advantage and self-renewal ability. The emergence of LSCs is a multi-step event, including genetic diversifcation and clonal selection, resulting in genetic heterogeneity among leukemic cells. LSCs generally exist in the immature CD34+CD38- leukemic population in most cases of AML and share some features with normal HSCs. However, recent studies have shown that in acute lymphoblastic leukemia (ALL), LSCs exist in B-lineagecommitted progenitors expressing CD19. In contrast to that in AML, in which LSCs generate leukemic cells in a hierarchical order with LSCs at the top, leukemia propagation in ALL is better explained by a stochastic model.