In the mouse blastocyst, epiblast cells are newly formed shortly before 
implantation. They possess a unique developmental plasticity, termed naive 
pluripotency. For development to proceed, this naive state must be subsumed by 
multi-lineage differentiation within 72 h following implantation. In vitro 
differentiation of naive embryonic stem cells (ESCs) cultured in controlled 
conditions provides a tractable system to dissect and understand the process of 
exit from naive pluripotency and entry into lineage specification. Exploitation 
of this system in recent large-scale RNAi and mutagenesis screens has uncovered 
multiple new factors and modules that drive or facilitate progression out of the 
naive state. Notably, these studies show that the transcription factor network 
that governs the naive state is rapidly dismantled prior to upregulation of 
lineage specification markers, creating an intermediate state that we term 
formative pluripotency. Here, we summarize these findings and propose a road map 
for state transitions in ESC differentiation that reflects the orderly dynamics 
of epiblast progression in the embryo.