The Lin(-)c-Kit(+) Sca-1(+) cell population in the bone marrow (BM) serves as the direct precursor for differentiation of myeloid cells. In this study, we report that deficiency in Fpr2, a G protein-coupled chemoattractant receptor in mice, is associated with reduced BM nucleated cells, including CD31(+)Ly6C(+) (granulocytes and monocytes), CD31(-)/Ly6C(int) (granuloid cells), and CD31(-)/Ly6C(high) (predominantly monocytes) cells. In particular, the number of Lin(-)c-Kit(+)Sca-1(+) (LKS) cells was reduced in Fpr2(-/-) mouse BM. This was supported by observations of the reduced incorporation of intraperitoneally injected bromodeoxyuridine by cells in the c-Kit(+) population from Fpr2(-/-) mouse BM. Purified c-Kit(+) cells from Fpr2(-/-) mice showed reduced expansion when cultured in vitro with stem cell factor (SCF). SCF/c-Kit-mediated phosphorylation of P38, STAT1, Akt (Thr-308), and Akt (Ser-473) was also significantly reduced in c-Kit(+) cells from Fpr2(-/-) mice. Furthermore, Fpr2 agonists enhanced SCF-induced proliferation of c-Kit(+) cells. Colony-forming unit assays revealed that CFU-granulocyte-macrophage formation of BM cells from Fpr2(-/-) mice was significantly reduced. After heat-inactivated bacterial stimulation in the airway, the expansion of c-kit(+) Sca-1(+) cells in BM and recruitment of Ly6G(+) cells to the lungs and CD11b(+)Ly6C(+)TNF(+) cells to the spleen of Fpr2(-/-) mice was significantly reduced. These results demonstrate an important role for Fpr2 in the development of myeloid lineage precursors in mouse BM.