Stem cell in vitro culture is a useful model system to study mechanisms underlying transitions between defined cell states. Epiblast stem cells, in addition to being capable of somatic differentiation, can be converted to a more primitive embryonic stem cell-like state, by overexpression of specific transcription factors. Here, we describe a reliable method to accomplish—and potentially further study—the transgene-independent reversion from epiblast stem cells to ES cells using administration of specific growth factors and small molecule inhibitors.