Epigenetic mechanisms control the combination of genes that are switched on and off in any given cell. In turn, this combination, called the transcriptional program, determines the identity and the fate of cells, which are deregulated in diseases such as cancer, inflammation, or neurological disorders. Chemical modifications (such as methylation or acetylation) of chromatin—an ensemble of nuclear factors, especially histone proteins around which DNA is wrapped—act as epigenetic signals. Enzymes that write or erase these chemical “marks,” and proteins that bind and interpret them, represent an important target class for drugs (1). On page 291 of this issue, Jiao and Liu (2) report the crystal structure of one prominent such enzyme called enhancer of zeste homolog 2 (Ezh2) in complex with obligatory protein binding partners. This structure, which has been largely elusive, provides clarity on the regulation of EZH2 catalytic activity and is an important step toward rational drug design.