AbstractAlthough several mitogens and survival factors have been previously shown to act on primordial germ cells (PGCs) in culture, it is not clear whether they are responsible for controlling proliferation of PGCs in the embryo. We show here that during their migratory phase, PGCs do not express FGF‐4, FGF‐8, or FGF‐17, but these FGFs are expressed by neighboring cells. Thus, any FGF action on migrating PGCs would appear to be through a paracrine mechanism. We found that after entering into the gonads, PGCs start to express FGF‐4 and FGF‐8. On this basis, we hypothesize that FGF signaling is involved in both a paracrine manner in initiating PGC proliferation during their migration and an autocrine manner in sustaining PGC proliferation after their arrival in the gonads. We then studied the role of soluble stem cell factor (SCF), which acts as a survival factor or a mitogen in culture, to determine whether it interacts with FGFs. We found that SCF has a complex effect on PGC proliferation. On one hand, soluble SCF promoted PGC proliferation synergistically with FGF in the absence of membrane‐bound SCF. Conversely, soluble SCF inhibited FGF‐stimulated proliferation of PGCs in the presence of membrane‐bound SCF. We account for these findings in a model involving regulation of PGC proliferation, in which SCF modulates the response to FGFs. Mol. Reprod. Dev. 68: 5–16, 2004. © 2004 Wiley‐Liss, Inc.