Mouse embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs) correspond to the naïve ground state of the preimplantation epiblast and the primed state of the post-implantation epiblast, respectively. The ESC state is characterised by spontaneous, reversible differences among the ESCs in their susceptibility to self-renewal and differentiation signals. Here (p. 43), Antonio Simeone and colleagues investigate the mechanisms that control this metastable state and the transition from ESCs to EpiSCs. The researchers report that Otx2, a transcription factor that is required for brain development, is expressed in a large subset of ESCs and maintains the ESC metastable state by antagonising ground state pluripotency and promoting commitment to differentiation. Otx2 is also needed for ESC transition into EpiSCs, they report, and stabilises the EpiSC state in cooperation with BMP4 and Fgf2. Finally, they show that Otx2 is required for the differentiation of ESC-derived neural progenitors. Thus, Otx2 is an intrinsic determinant of the ESC state and of the ESC to EpiSC pluripotency transition.