Chromatin-modifying enzymes are known to be critical components for the correct differentiation of embryonic stem cells into specific lineages, such as neurons. Recently, the role of Polycomb group proteins has been studied in the specification and differentiation of muscle stem cells. In this perspective, we review a recent study by Juan and colleagues (pp. 789-794) in Genes & Development of the role of the polycomb group protein Ezh2 in muscle stem cells, and discuss the implications for general lineage restriction.