It has been demonstrated that several types of somatic stem cells have the remarkable capacity to differentiate into other types of tissues. We demonstrate here that stem cells from the skin, the largest organ of the body, have the capacity to form multiple cell lineages during development. Using our recently developed sorting technique, we isolated viable homogenous populations of somatic epidermal stem and transient amplifying cells from the skin of 3-day old transgenic mice, who carried the enhanced green fluorescent protein transgene, and injected stem, TA, or unsorted basal epidermal cells into 3.5-day C57BL/6 blastocysts. Only the stem-injected blastocysts produced mice with GFP⁺ cells in their tissues. We found GFP⁺ cells in ectodermal, mesenchymal, and neural-crest-derived tissues in E13.5 embryos, 13-day-old neonates, and 60-day-old adult mice, proving that epidermal stem cells survived the blastocyst injection and multiplied during development. Furthermore, the injected stem cells altered their epidermal phenotype and expressed the appropriate proteins for the tissues into which they developed, demonstrating that somatic epidermal stem cells have the ability to produce cells of different lineages during development. These data suggest that somatic epidermal stem cells may show a generalized plasticity expected only of embryonic stem cells and that environmental (extrinsic) factors may influence the lineage pathway for somatic stem cells. Thus, the skin could be a source of easily accessible stem cells that are able to be reprogrammed to form multiple cell lineages.