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’nature of hematopoietic stem cells (HSC), their phenotype, loca-tions, regulators, and functional potential. A complex net of dynamic interactions has been revealed, indicating that this unique hybrid system is regulated in a cooperative and recipro-cal manner with other systems in the body. It should be noted that HSC populations are largely heterogeneous and often con-tain subsets of more mature progenitors. Thus, in many cases within the published literature, combined stem and progenitor cells (HSPC) have been examined rather than more purified pop-ulations of HSC. Studies that have examined HSC demonstrate that stem cells must be considered in the context of their micro-environment. Recent publications describe reciprocal regulatory effects between players, both cellular and extracellular, across systems that had once been believed to be distinct. The following examples may better demonstrate this progres-sion in conventional thinking and illustrate the intersystem regu-lation of HSPC. In the seventies, the existence of stem cell niches that regulate HSPC was suggested (Schofield, 1978). The bone marrow (BM) stromal microenvironment was reported to exert selective inhibitory regulation on adherent progenitors, prevent-ing their differentiation while promoting their proliferation poten-tial (Zipori and Sasson, 1980). These and other studies paved the way for more recent findings, discussed later in this review, that impact on niche-supporting stromal cells