BRD4 is a member of the bromodomain and extra-terminal (BET) family of proteins, which regulate gene transcription through interactions with acetylated histones. Previous studies have shown that control of histone acetylation is essential for blastula pluripotency and development of the neural crest, a vertebrate-specific stem cell population. Although BRD4 has been implicated in neural crest differentiation, whether BET proteins contribute to the transition of pluripotent embryonic cells into neural crest cells remains unknown. Here, Carole LaBonne and colleagues show that inhibiting BET protein activity in Xenopus laevis embryos leads to complete loss or severe reduction of pluripotency markers and hinders the establishment of a neural crest progenitor. They find that, among BET proteins, BRD4 controls pluripotency in blastula cells and enables the transition of these stem cells to lineage-restricted states. Interestingly, blocking BET at blastula states prolongs the competence of cells to transit to a neural progenitor state. Overall, this work reveals how the BET family of epigenetic markers controls maintenance of pluripotency and establishment of neural crest stem cells.