Embryonic stem (ES) cells possess a globally open, decondensed chromatin structure that, together with trans-acting factors, supports transcriptional competence of developmentally regulated genes. However, our understanding of the mechanisms that establish transcriptional competence of specific genes is limited. In this issue of Genes & Development, Xu and colleagues (pp. 2824–2838) show that tissue-specific enhancers are actively marked by an unmethylated window in ES cells and induced pluripotent stem (iPS) cells. They propose a model and present supporting evidence to demonstrate the active involvement of pioneer transcription factors in this process. This work marks an important step toward the understanding of the mechanisms that define and maintain pluripotency, and calls for the identification of the factors that participate in the establishment of transcriptional competence in pluripotent cells.