Acute leukemias are the result of aberrant hematopoietic processes initiated by rare leukemia stem cells that have maintained or acquired the capacity of indefinite proliferation through accumulated mutations and/or epigenetic changes. The most likely view of hematopoietic cell lineage organization is that of complex reactive or adaptative systems. The properties of leukemia stem cells indicate that current chemotherapy will not be effective. Furthermore, recent advances indicate that stem cell microenvironment directly affects cell fate decisions. Because they are quiescent, leukemia stem cells do not respond to cell cycle-specific cytotoxic agents used in treating leukemia, which contribute to treatment failure. New strategies are required that specifically target the malignant stem cell population.