Hematopoietic stem cells (HSCs) reside in specialized bone marrow (BM) niches regulated  by the sympathetic nervous system (SNS). Here, we have examined whether mononuclear  phagocytes modulate the HSC niche. We defined three populations of BM mononuclear  phagocytes that include Gr-1^hi monocytes (MOs), Gr-1^lo MOs, and macrophages (MΦ)  based on differential expression of Gr-1, CD115, F4/80, and CD169. Using MO and MΦ conditional depletion models, we 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⁺ MΦ, which spares BM MOs, was sufficient to induce HSC/progenitor egress. MΦ 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 MΦ cross talk with the Nestin⁺niche cell promotes retention,  and in contrast, SNS signals enhance egress. Thus, strategies that target BM MΦ hold the  potential to augment stem cell yields in patients that mobilize HSCs/progenitors poorly.