AbstractIn eukaryotic cells, gene expression is not only regulated by transcription factors but also by several epigenetic mechanisms including post‐translational modifications of histone proteins. There are numerous histone modifications described to date and methylation, acetylation, ubiquitination and phosphorylation are amongst the best studied. In parallel, certain viruses interact with the very same regulatory mechanisms, hereby manipulating the normal epigenetic landscape of the host cell, to fit their own replication needs. This review concentrates on herpesviruses specifically and how they interfere with the histone‐modifying enzymes to regulate their replication cycles. Herpesviruses vary greatly with respect to the cell types they infect and the clinical diseases they cause, yet they share various common features including their capacity to encode viral proteins which affect and interfere with the normal functions of histone‐modifying enzymes. Studying the epigenetic manipulation/dysregulation of herpesvirus–host interactions not only generates novel insights into the pathogenesis of these viruses but may also have important therapeutic implications.