Plasticity in early embryonic populations and stem cells explains both differentiation competence and regeneration. How is plasticity supported? I will discuss different stories that emphasize a common theme, that plasticity and cellular memory is supported by transcription factor occupancy. We found that the binding of conventional sequence specific transcription factors (TFs) is often insufficient to promote transcription of the genes in their vicinity, but that changes in actual transcription are a response to alterations in signaling. As a result, TFs can be seen as competence factors for lineage specific differentiation organizing enhancer networks for response to different signals. Moreover, when differentiation begins, the majority of sequence specific TFs remain bound at their ‘former,’ targets, where they preserve plasticity and reversibility. In the instance of early mammalian development, the final of the three blastocyst lineages to be specified, the Primitive Endoderm (PrE), but despite PrE being last, we find that fully specified isolated PrE is sufficient to regenerate entire embryos and in fact born mice. As with differentiation, it is the expression of specific TFs, or their persistence of them at a protein level, that sustains multiple enhancer networks in these cells, enabling PrE to reconstruct a complete embryo in the presence of appropriate signaling.