The primitive endoderm (PrE, also named hypoblast), a predominantly extraembryonic epithelium that arises from the inner cell mass (ICM) of the mammalian pre-implantation blastocyst, plays a fundamental role in embryonic development, giving rise to the yolk sac, establishing the anterior–posterior axis and contributing to the gut. PrE is specified from the ICM at the same time as the epiblast (Epi) that will form the embryo proper. While in vitro cell lines resembling the pluripotent Epi have been derived from a variety of conditions, only one model system currently exists for the PrE, naïve extraembryonic endoderm (nEnd). As a result, considerably more is known about the gene regulatory networks and signalling requirements of pluripotent stem cells than nEnd. In this review, we describe the ontogeny and differentiation of the PrE or hypoblast in mouse and primate and then discuss in vitro cell culture models for different extraembryonic endodermal cell types.