Despite two decades of effort, establishment of pluripotent embryonic stem cells (ESC) from ungulates such as cattle and pigs has remained an elusive goal, with true ESC only successfully isolated from rodents and primates. The many reports describing ESC-like cultures from other “difficult” species has largely depended upon adopting strategies successful for mouse and human and have not yet produced a cell type that both proliferated continuously in culture without differentiation and demonstrated full pluripotent potential. These difficulties may have been exacerbated in ungulates by the lack of specific markers exclusive to inner cell mass (ICM) and its derivative the epiblast and by unique features of their preimplantation development. Especially important may have been the choice of culture condition, including growth factors, for establishing and sustaining the ESC. Recent modifications to culture medium, notably the inclusion of particular protein kinase inhibitors, have permitted ESC derivation from rat and previously “non-permissive” mouse strains. These conditions appear to stabilize the biochemical networks that sustain pluripotency and to render the cells dependent upon LIF signaling. In addition, the recent successful generation of induced pluripotent stem cells (iPSC) from pig by procedures that should be easily adapted to other species, is also likely to advance the area quickly. The pig is a particularly desirable species to create pluripotent cell lines because of its value as a biomedical model in transplantation at a time when there is mounting pressure to rush stem cells to the clinic before their safety has been adequately tested in animals.