Abstract Chronic myeloid leukemia (CML) is a stem cell-derived leukemia in which neoplastic cells exhibit the Philadelphia (Ph) chromosome and the related oncoprotein, BCR-ABL1. The disease is characterized by an accumulation of myeloid precursor cells in the peripheral blood (PB) and bone marrow (BM). A small fraction of neoplastic cells in the CML clone supposedly exhibits self-renewal and thus long-term disease-propagating ability. However, so far, little is known about the phenotype, function, and target expression-profiles of these leukemic stem cells (LSC). Recent data suggest that CML LSC aberrantly express the interleukin-2 receptor alpha chain CD25. Whereas normal CD34+ /CD38− BM stem cells display only low amounts of CD25 or lack CD25, CD34+ /CD38− LSC strongly express CD25 in over 90% of all patients with untreated CML. As a result, CD25 can be employed to identify and quantify CML LSC. In addition, it has been described that CD25 serves as a negative growth regulator of CML LSC. In the current article, we review the value of CD25 as a novel marker and potential drug-target in CML LSC.