Most hematopoietic malignancies are comprised of cells that are functionally heterogeneous with only a subset being responsible for tumor maintenance. These cancer stem cells are so named because they possess qualities reminiscent of normal tissue stem cells including self-renewal, prolonged survival, and the ability to give rise to cells with more differentiated characteristics. Effort is now focused on identifying cancer stem cells in various hematopoietic malignancies, and defining the cells of origin such that the stepwise accumulation of genetic/epigenetic events necessary for cancer stem cell development can be delineated. A detailed understanding of these processes could lead to development of therapeutics that more effectively treat hematopoietic malignancies and potentially other cancers.