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Germ cells, preimplantation embryos and pluripotent stem cells at first glance seem to have nothing in common. A more careful look, though, reveals that they are very closely linked to each other. The zygote originates from the fusion of two highly specialized germ cells (the sperm and the oocyte) and in a few days develops into a blastocyst with a pluripotent cell population (the inner cell mass). These cells diverge from the extraembryonic cells of the trophoectoderm and can give rise to embryonic stem cells, in which a perpetual pluripotent and undifferentiated state is maintained.The correct establishment of pluripotency guarantees the correct onset of development and therefore its acquisition is a fundamental biological process; any mistake associated with it has profound impact on gestation. A detailed understanding of the mechanisms that induce and regulate pluripotency is critical for the basic understanding of fundamental developmental processes that depend from it like the onset of differentiation and cellular plasticity. This is particularly relevant in consideration of the potential clinical application of human pluripotent stem cells (hPSCs).