Recent studies have demonstrated that tumor cells have hierarchical organization with cancer stem cells at the apex. Cancer stem cells, also termed cancer initiating cells, have self-renewal capacity and might not be sensitive to cytotoxic drugs. Thus, these cells may be responsible for the high frequency of relapse in many cancers, such as acute leukemias, brain and breast cancer. This chapter will approach the evidences of the presence of leukemia stem cells and the therapeutic perspectives to reach these cells. © 2012 Bentham Science Publishers. 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