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The balance between active and repressive chromatin is central to lineage differentiation in mammals. Dysregulation of this process leads to pathogenic conditions such as developmental disorders or cancer. Post-translational modifications (PTMs) of histones play pivotal roles in the establishment of active and chromatin domains. However, how histone-modifying enzymes are orchestrated to place active or repressive histone PTMs at desired loci still remains not fully understood. Intriguingly, our past and current work uncovered distinct regulatory mechanisms that license the catalytic activity of active versus repressive histone-modifying enzymes, providing a molecular basis of how a chromatin state is determined in mammalian cells.