An important question in cell biology is how the fate of cells becomes restricted with differentiation. During development, cells acquire a number of epigenetic modifications that define their differentiated identity and prevent their conversion to another cell fate. The histone variant macroH2A is involved in the gene silencing that maintains the inactive X chromosome, and also has been shown to restrict tumour development, but it is not known whether it also has a role in restricting cell fate changes. Here (p. 6094), Vincent Pasque and colleagues characterise the expression pattern of macroH2A.1 during mouse embryogenesis and find that it is expressed only at low levels in the pluripotent cells of the inner cell mass and epiblasts, but at high levels in differentiated somatic cells. Using chromatin immunoprecipitation, they show that, during development, macroH2A.1 is incorporated into pluripotent genes in somatic cells but not in embryonic stem cells. Importantly, when macroH2A.1 or macroH2A.2 are depleted in a neural stem cell line, an increased efficiency of pluripotency gene reactivation and somatic cell reprogramming to pluripotency is seen. Conversely, overexpression of macroH2A prevented the conversion of epiblast stem cells to naïve pluripotency. Taken together, the authors provide evidence that this mark is an epigenetic barrier to pluripotency that stabilises the differentiated cell state.