In female mammals, one X chromosome is epigenetically silenced in adult cells by the process of X inactivation (Xi). However, in the pluripotent epiblast cells of the preimplantation mouse embryo, both X chromosomes are active and Xi of the paternal or maternal X occurs at random shortly after implantation (random Xi). By contrast, in very early mouse embryos (and in extra-embryonic lineages), the paternal X chromosome is selectively inactivated (imprinted Xi). So when exactly does the mode of Xi change from imprinted to random during development? On p. 197, Hitoshi Niwa and colleagues examine Xi during the differentiation of inner cell mass (ICM)-derived female mouse embryonic stem (ES) cells. The researchers use forced expression of Cdx2 and Gata6 to induce ES cell differentiation toward trophectoderm (TE) and primitive endoderm (PrE), respectively. They report that random Xi occurs in both TE and PrE cells and in the TE of cloned embryos derived from female ES cells, suggesting that all marks for imprinted Xi must be erased by the time the ICM forms.