The functionality of a cell's genome is controlled epigenetically on the level of chromatin. Multiple post-translational modifications of histone proteins together with DNA methylation play a key role in directing distinct functional states of chromatin. As it emerges, many epigenetic marks on the chromatin platform do not act independently, but cross-talk with each other. In this issue of Genes & Development, Adhvaryu and Selker (3391-3396) provide novel insights into an intricate regulatory network involving histone phosphorylation, histone methylation, and DNA methylation.​