Histone proteins are major determinants of gene regulation, and histone mimicry allows viruses to gain control of gene regulatory functions to support viral replication or suppress host antiviral responses. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been shown to disrupt host cell epigenetic regulation, but the underlying mechanisms are unknown. In a recent study, Kee et al. uncover that the viral ORF8 protein mimics the H3 histone protein to disrupt epigenetic regulation. The authors found that, during infection, ORF8 associates with chromatin, disrupts the post-translational modification of histones and promotes chromatin compaction. Viruses that lacked ORF8 or the histone mimic site had a reduced ability to disrupt host chromatin, and host cells infected with these viruses had an altered transcriptional response to infection and a lower viral genome copy number compared with wild-type viruses. These data may explain why SARS-CoV-2 viruses lacking ORF8 have been associated with a reduced severity of COVID-19.