The concept of leukemic stem cells (LSC) is increasingly employed to explain the biology of various myeloid neoplasms and to screen for essential targets, with the hope to improve drug therapy through elimination of disease-initiating cells. Although the stem cell hypothesis may apply to all neoplasms, leukemia-initiating cells have so far only been characterized in some detail in advanced acute (AML) and chronic myeloid leukemia (CML). An intriguing observation is that although expressing various targets, LSC often remain unresponsive against most drugs, presumably because of 'intrinsic' resistance. Moreover, LSC represent heterogeneous populations of cells, grow in separate subclones, and acquire numerous defects, which points to substantial genetic instability and stem cell plasticity. The situation is complicated by the fact that stem cell evolution is a step-wise process with variable latency periods, so that many LSC-derived subclones remain small (undetectable) at diagnosis, but later, during therapy, may expand to a dominant clone and clinically overt relapsing disease. Finally the interaction between LSC and the microenvironment may contribute to stem cell function and LSC resistance. Taking all these considerations into account, the application of broadly acting targeted drugs and of drug combinations has been proposed in order to better suppress or even eliminate LSC in AML and CML. The current article provides a summary of our knowledge on LSC in various myeloid neoplasms with special reference to novel arising treatment concepts.