The xenotransplantation model has been instrumental for the identification and characterization of human leukemic stem cells. In this chapter we will discuss the development of the immunodeficient model in the understanding of leukemogenesis, describe the different models of immunodeficiency now available and their values, as well as describe the methods used for the purification of LSCs. We will concentrate on the model of acute myeloid leukemia, as it was the first type of leukemia for which the xenotransplantation model was developed.