Fgf8 exerts a strong effect on the mesenchymal cells of neural crest (NC) origin that are fated to form the facial skeleton. Surgical extirpation of facial skeletogenic NC domain (including mid-diencephalon down through rhombomere 2), which does not express Hox genes, results in the failure of facial skeleton development and inhibition of the closure of the forebrain neural tube, while Fgf8 expression in the telencephalon and in the branchial arch (BA) ectoderm is abolished. We demonstrate here that ( i ) exogenous FGF8 is able to rescue facial skeleton development by promoting the proliferation of NC cells from a single rhombomere, r3, which in normal development contributes only marginally to mesenchyme of BA1, and ( ii ) expression of Fgf8 in forebrain and in BA ectoderm is subjected to signal(s) arising from NC cells, thus showing that the development of cephalic NC-derived structures depends on FGF8 signaling, which is itself triggered by the NC cells.