For many years it has been clear that embryonic cells from different mouse strains differ in their properties for generating embryonic stem cells (ESCs). Specifically, ESCs can be generated and maintained from some (‘permissive’) strains in the presence of serum and LIF, whereas these conditions are insufficient to support self-renewal of cells derived from other genetic backgrounds (‘non-permissive’ strains). Here (p. 431), Satoshi Ohtsuka and Hitoshi Niwa set out to understand the reasons behind the differing potential of ESCs from different origins, and find that this can be traced back to differential LIF responsiveness. They observed that LIF treatment induces higher JAK-Stat pathway activity at early time points, and lower MAPK activation at later time points, in permissive strains than non-permissive ones. This difference is functionally important, since ectopic activation of Stat3 in ESCs from non-permissive strains promotes their self-renewal. Although the downstream outputs regulated by the balance of these two pathways have yet to be fully analysed, these experiments reveal important differences in the cellular responses that underlie the differing properties of ESCs from different genetic backgrounds.