Embryonic Stem Cells (ESCs) can self renew or differentiate into all cell types, a phenomenon known as pluripotency. Distinct pluripotent states have been described, termed “naive” and “primed” pluripotency. The mechanisms that control naive‐primed transition are poorly understood. Here, we perform a targeted screen for kinase inhibitors which modulate the naive‐ primed pluripotent transition. We find that selective inhibitors targeting the Erk5 kinase and BET bromodomain family proteins drive ESCs towards primed pluripotency. Using compound selectivity engineering and CRISPR/Cas9 genome editing, we reveal distinct functions for Erk5 and Brd4 in pluripotency regulation. We show that Erk5 signalling maintains ESCs in the naive state, and suppresses progression towards primed pluripotency and neuroectoderm differentiation. Additionally, we identify a specialised role for Erk5 in defining ESC lineage selection, whereby Erk5 inhibits a cardiomyocyte specific differentiation programme. Our data therefore reveal multiple critical functions for Erk5 in controlling ESC identity.