The fibroblast growth factors (FGFs) are a group of at least 25 structurally related peptides that are involved in many biological processes. Some FGFs are active in bone, including FGF-1, FGF-2, FGF-18 and recent evidence indicates that FGF-8 is osteogenic, particularly in mesenchymal stem cells. In the current study, we found that FGF-8 was expressed in rat primary osteoblasts, and in osteoblastic UMR-106 and MC3T3-E1 cells. Both FGF-8a and FGF-8b potently stimulated the proliferation of osteoblastic cells, while inhibiting the formation of mineralized bone nodules in long term cultures of osteoblasts and reducing the levels of osteoblast differentiation markers, osteocalcin and bone sialoprotein. FGF-8a induced the phosphorylation of p42/p44 mitogen-activated protein kinase (MAPK) in osteoblastic cells, however its mitogenic actions were not blocked by either the MAPK kinase (MEK) inhibitor, U0126, nor the PI3 kinase (PI3K) inhibitor, Ly294002. Interestingly, FGF-8a, unlike FGF-8b and other members of the family, inhibited osteoclastogenesis in mouse bone marrow cultures and this was via a receptor activator of NFB Ligand (RANKL)/osteoprotegerin (OPG) independendent-manner. However, FGF-8a did not affect osteoclastogenesis in RAW_264.7 cells (a macrophage cell line, devoid of stromal-cells) exogenously stimulated by RANKL nor did it effect mature osteoclast function, as assessed in rat calvarial organ cultures and isolated mature osteoclasts. In summary, we have demonstrated that FGF-8 is active in bone cells, stimulating osteoblast proliferation in a MAPK-independent pathway and inhibiting osteoclastogenesis via a RANKL/OPG-independent mechanism. These data suggest that FGF-8 may have a physiological role in bone acting in an autocrine/paracrine manner.