The embryogenesis of normal human skin is a complex process involving multiple cell types and developmentally regulated growth factors. The immunohistochemical localization of epidermal growth factor receptors (EGF-R) was studied in human fetal skin because this receptor modulates all known actions of EGF and TGF-alpha. EGF-R are present in developing skin as early as the 42nd day of gestation. Immunoreactive EGF-R are present in keratinocytes, endothelial, and skeletal muscle cells. In contrast to normal adult human skin in which the EGF-R are primarily restricted to the basal and immediately suprabasal keratinocytes, the fetal epidermis showed a persistent expression of EGF-R in all cell layers. The absence of EGF-R on the outer, apical surface of periderm cells that are exposed to amniotic fluid was unexpected and may reflect down-regulation of EGF-R by EGF/TGF-alpha or related fetal growth factors present in amniotic fluid. The complex regulation of EGF-R in embryonic hair follicles and sebaceous glands indicates an active and perhaps regulatory role for EGF/TGF-alpha in the development and function of pilosebaceous glands as well as mammalian skin in general.