The mouse hematopoietic stem cell (HSC) is probably the best-understood somatic stem cell in higher organisms. Recent studies have shown that the highest self-renewal potential is most likely contained within an exceedingly small number of deeply dormant bone marrow HSCs. These stem cells are housed in individual niches that preserve their dormancy via signaling molecules such as Thrombopoietin, Angiopoietins, and Stem Cell Factor. In response to injury cues, dormant HSCs are efficiently activated and produce numerous progenitors and mature cells. A series of intracellular regulatory molecules including FoxOs, mTORC1, Fbw7, Egr1, Pbx1, pRb, c-Cbl, Myc, and Bmi1 mediate the processes of dormancy, cycling, self-renewal, differentiation, and survival, all of which control the behavior of HSCs.