Recent discoveries indicate that hematopoietic stem cells have limits on their proliferative capacity and are unable to divide indefinitely. There is great heterogeneity within the compartment as to the extent of this proliferative limitation. At any given time it appears that hematopoiesis is maintained by the progeny of only a few stem cells. When these are exhausted the progeny from other stem cells take their place. The observations of proliferative limitation, heterogeneity, and clonal succession must be incorporated into any model of stem cell organization. These new discoveries and the models incorporating them have important clinical implications. They may explain the inability of normal tissues to develop drug resistance and they also offer a mechanism by which cell renewal systems decrease the development of malignancies. In the selection of chemotherapeutic agents not only the effectiveness of the drug upon the tumor must be considered, but also how specific agents affect the stem cell compartment. These data have important implications in the use of bone marrow transplantation for both malignant and nonmalignant disease.