Experimental models that allow the evaluation of the full potential of stem cells under normal physiological conditions and in the absence of genetic or injury-induced dysfunction would serve as valuable tools for the study of the mechanisms underlying stem cell differentiation. Ideally, such a model would also permit the robust formation of donor-derived tissue-specific cells. Because studies have shown that the differentiation of stem cells into cells of a different germinal layer is highly inefficient in the absence of selective pressure, it is very unlikely that a healthy adult animal can fulfill these requirements. In this review, we describe the advantages of the permissive aspects of the developing preimmune fetus in the early gestational age that led us to develop the sheep as a large-animal model of human stem cell plasticity.