The integration of X-inactivation with development is a crucial aspect of this classical paradigm of epigenetic regulation. During early female mouse development, X-inactivation reprogramming occurs in pluripotent cells of the inner cell mass of the blastocyst and in pluripotent primordial germ cells. Here we discuss the developmental strategies which ensure the coupling of the regulation of X-inactivation to the acquisition of pluripotency through the regulation of the master of X-inactivation, the non-coding Xist gene, by the key factors which support pluripotency Nanog, Oct4 and Sox2.