The striking similarity between mesodermally derived fibroblasts and ectomesenchyme cells, which are thought to be derivatives of the neural crest, has long been a source of interest and controversy. In mice, the gene encoding the alpha subunit of the platelet-derived growth factor receptor (PDGFRα) is expressed both by mesodermally derived mesenchymal cells and by ectomesenchyme. Whole-mount immunostaining previously revealed that PDGFRα is present in the cephalic neural fold epithelium of early murine embryos (Takakura et al.  J Histochem Cytochem 45:883–893). We now show that, within the neural fold, a sharp boundary exists between E-cadherin–expressing non-neural epithelium and the neural epithelium of the dorsal ridge. In addition, we found that cells coexpressing E-cadherin and PDGFRα are present in the non-neural epithelium of the neural folds. These observations raise the possibility that at least some PDGFRα+ ectomesenchyme originates from the lateral non-neural domain of neural fold epithelium. This inference is consistent with previous reports (Nichols [ 1981] J Embryol Exp Morphol 64:105–120; Nichols [ 1986] Am J Anat 176:221–231) that mesenchymal cells emerge precociously from an epithelial neural fold domain resembling the primitive streak in the early embryonic epiblast. Therefore, we propose the name “metablast” for this non-neural epithelial domain to indicate that it is the site of a delayed local delamination of mesenchyme similar to involution of mesoderm during gastrulation. We further propose the testable hypothesis that neural crest and ectomesenchyme are developmentally distinct progenitor populations and that at least some ectomesenchyme is metablast-derived rather than neural crest-derived tissue. Developmental Dynamics 229:118–130, 2004. © 2003 Wiley-Liss, Inc.