In the head, neural crest cells generate ectomesenchymal derivatives: cartilage, bone, and connective tissue. Indeed, these cells generate much of the cranial skeleton. There have, however, been few studies of how this lineage is established. Here, we show that neural crest cells stop expressing early neural crest markers upon entering the pharyngeal arches and switch to become ectomesenchymal. By contrast, those neural crest cells that do not enter the arches persist in their expression of early neural crest markers. We further show that fibroblast growth factor (FGF) signaling is involved in directing neural crest cells to become ectomesenchymal. If neural crest cells are rendered insensitive to FGFs, they persist in their expression of early neural crest markers, even after entering the pharyngeal arches. However, our results further suggest that, although FGF signaling is required for the realization of the ectomesenchymal lineages, other cues from the pharyngeal epithelia are also likely to be involved. Developmental Dynamics 237:592–601, 2008. © 2008 Wiley-Liss, Inc.