Hematopoietic stem cells, which share with other stem cells of adult tissues the ability to maintain constant the number and diversity of differentiated mature cells throughout adult life offer a fabulous system to analyze mechanisms controlling cell proliferation and differentiation. Cytokines controlling the differentiation of intermediate progenitors into mature cells of the various lineages have been characterized and have been widely used, in vitro as in vivo, to increase the output of differentiated cells. In contrast, despite significant technological advances, molecular events associated with the stem cell decisions first to either self-renew or differentiate, and then to irreversibly commit to one of the lymphoid or of the myeloid pathways are still very badly understood. This is partly explained by the lack of reliable assays, particularly in humans, to assess stem cell activity, and by the difficulty to dissect the composition of molecular complexes regulating gene expression in these very rare cells. Despite these limitations, recent evidence suggests that there is some flexibility in the initial decisions of stem cells, and that extracellular factors may influence stem cell fate. If this is confirmed, it may then become possible to propose new therapeutic strategies based on the manipulation of stem cell properties.