Leukemia can be viewed as a newly formed, abnormal hematopoietic tissue initiated by a few leukemic stem cells (LSCs) that undergo an aberrant and poorly regulated process of organogenesis analogous to that of normal hematopoietic stem cells. A hallmark of all cancers is the capacity for unlimited self-renewal, which is also a defining characteristic of normal stem cells. Given this shared attribute, it has been proposed that leukemias may be initiated by transforming events that take place in hematopoietic stem cells. Alternatively, leukemias may also arise from more committed progenitors caused by mutations and/or selective expression of genes that enhance their otherwise limited self-renewal capabilities. Identifying the LSCs for each type of leukemia is a current challenge and a critical step in understanding their respective biologies and may provide key insights into more effective treatments. Moreover, LSC identification and purification will provide a powerful diagnostic, prognostic, and therapeutic tool in the clinic.