Hematopoietic stem cells (HSCs) reside in specialized bone marrow niches regulated by the sympathetic nervous system. In this paper, AECC member and Einstein Stem Cell Institute director, Frenette, and his collaborators examined whether mononuclear phagocytes modulate the HSC niche. Three populations of BM mononuclear phagocytes were examined: Gr-1(hi) monocytes (MOs), Gr-1(lo) MOs, and macrophages (MPhi) based on differential expression of Gr-1, CD115, F4/80, and CD169. Using MO and MPhi conditional depletion models, he found that reductions in BM mononuclear phagocytes led to reduced BM CXCL12 levels, the selective down-regulation of HSC retention genes in Nestin(+) niche cells, and egress of HSCs/progenitors to the bloodstream. Furthermore, specific depletion of CD169(+) MPhi, which spared BM MOs, was sufficient to induce HSC/progenitor egress. MPhi depletion also enhanced mobilization induced by a CXCR4 antagonist or granulocyte colony-stimulating factor. These results highlight two antagonistic, tightly balanced pathways that regulate maintenance of HSCs/progenitors in the niche during homeostasis, in which MPhi cross talk with the Nestin(+) niche cell promotes retention, and in contrast, sympathetic nervous system signals enhance egress. Thus, strategies that target BM MPhi hold the potential to augment stem cell yields in patients that mobilize HSCs/progenitors poorly.