Epiblast stem cells (EpiSCs) are self-renewing multipotential cells that are derived from the postimplantation mouse embryos and they display innately different lineage propensity.  Blocking WNT signalling during the derivation and the maintenance of the EpiSCs enhances the predisposition for ectoderm differentiation.  Removal the blocking activity in these EpiSCs during culture re-wires the cells to the state of broad mesendoderm and ectoderm propensity typical of the conventional Blocking WNT signalling activity in the conventional EpiSCs has little effect on the lineage propensity.  The inability to re-wire the conventional EpiSCs suggests the lineage propensity of these EpiSCs are hard-wired in the context of modulation by WNT signalling.  Re-wiring of the conventional EpiSCs can be achieved by blocking Nodal activity. The Nodal-blocked EpiSCs acquire the propensity of surface ectoderm differentiation at the expense of the mesendoderm.  The enhancement of ectoderm propensity of the EpiSCs by blocking WNT or Nodal signalling mimics the in vivo setting that epiblast cells with prospective ectoderm fates are regionalized to the anterior epiblast of the embryo where there is low WNT and Nodal signalling activity.  Wiring the stem cells by priming with appropriate signalling activity provides an effective means to guide the first steps of cell differentiation for the generation of specific cell types.