Hematopoietic stem cells (HSCs) are characterized by their ability of self-renewal to replenish the stem cell pool and differentiation to more mature cells. The subsequent stages of progenitor cells also share some of this dual ability. It is yet unknown whether external signals modulate proliferation rate or rather the fraction of self-renewal. We propose three multicompartment models, which rely on a single external feedback mechanism. In Model 1 the signal enhances proliferation, whereas the self-renewal rates in all compartments are fixed. In Model 2 the signal regulates the rate of self-renewal, whereas the proliferation rate is unchanged. In Model 3, the signal regulates both proliferation and self-renewal rates. This study demonstrates that a unique strictly positive stable steady state can only be achieved by regulation of the rate of self-renewal. Furthermore, it requires a lower number of effective cell doublings. In order to maintain the stem cell pool, the self-renewal ratio of the HSC has to be > or =50% and it has to be higher than the self-renewal ratios of all downstream compartments. Interestingly, the equilibrium level of mature cells depends only on the parameters of self-renewal of HSC and it is independent of the parameters of dynamics of all upstream compartments. The model is compatible with the increase of leukocyte numbers following HSC transplantation. This study demonstrates that extrinsic regulation of the self-renewal rate of HSC is most essential in the process of hematopoiesis.