AbstractThere are three fetal membranes in mammals, namely the yolk sac, allantois and amnion, but only the first two form a placenta. In Monotremata (monotremes), Marsupialia (marsupials) and Placentalia (eutherians), the yolk sac transfers nutrients originating from uterine glandular secretion or the maternal blood. Ontogenetically, the yolk sac of most eutherians loses contact with the peripheral chorion and forms a free splanchnopleuric yolk sac that transfers substances from the exocoelomic cavity, not directly from the endometrium as in marsupials and rodents. This free yolk sac has been preserved in humans and substances originating from glandular secretions are transferred from the exocoelomic cavity to the embryo via this route. The therian yolk sac expresses numerous growth and transcription factors, associated binding proteins and receptors that control its differentiation and function, including hematopoiesis and angiogenesis. Errors in yolk sac development and function could contribute to embryonic malformation, miscarriage and growth diseases. Factors regulating transfer and metabolism, notably insulin and IGF2, are imprinted in the human yolk sac, as in all therians so far studied. This suggests persistence of a strong selective pressure for parentally controlled allocation of resources to the growing embryo via this fetal membrane. The metabolic and biosynthetic functions of the yolk sac of the ancestral therian stem species, as well as hematopoiesis in the eutherian ancestor, appear to have been retained by the human yolk sac. Thus, the yolk sac of humans, like that of all viviparous mammals, is a true placenta crucial for early embryonic development and survival. J. Exp. Zool. (Mol. Dev. Evol.) 312B:545–554, 2009. © 2008 Wiley‐Liss, Inc.