Pluripotency is a transient state in the early vertebrate embryo. As lineage restrictions progressively define and sub-define the tissues of the body, however, one remarkable group of cells retains earlier pluripotent characteristics. The neural crest is a progenitor population with the capacity to contribute to all vertebrate germ layers, and in Xenopus it is known to share transcription factor and signalling pathway activity with the blastula cells of the earlier embryo. However, the role of the epigenetic state – and in particular histone acetylation, a process regulated by histone deacetylases (HDACs) – in regulating neural crest pluripotency has remained incompletely understood. Now, Anjali Rao and Carole LaBonne use small molecule HDAC inhibitors to address this problem. HDAC inhibition at early gastrula stages leads to the loss of the neural crest, and impedes the induced reprogramming of explants to neural crest fates. In blastula cells, HDAC inhibitors cause a broad loss of pluripotency gene expression and the precocious co-expression of multiple lineage markers. At the chromatin level, histone acetylation levels increase as cells become lineage restricted, and are precociously increased following HDAC inhibition. Conversely, increasing the level of HDAC1 reduces acetylation, promotes maintenance of pluripotency markers and enhances neural crest reprogramming. Together, this work demonstrates a key role for histone deacetylation in pluripotency and the development of the neural crest.