In this issue, Li et al. reported the application of extended pluripotent stem (EPS) cells in generating gene-targeted mouse models, which permits direct and rapid constructing mouse models through tetraploid complementation. In the same issue, Du et al. reported efficient derivation of EPS cells from NOD-scid Il2rg^-/- mice, which are refractory to pluripotent cell establishment. Collectively, these two studies show the great potentials of EPS cells in generating mouse models and establishing pluripotent cells with non-permissive backgrounds, which highlight the possibility of using EPS technology to construct mouse models from refractory strains. The cover image shows that the mouse embryo is surrounded by the core four components of EPS culturing medium (LIF, CHIR 99021, DiM and MiH).