Using cryo-microscopy, researchers present a high-resolution structure of monkeypox virus DNA polymerase holoenzyme, a complex that plays a key role in the genome replication process of the virus. The findings reveal the mechanism that underlies monkeypox virus genome replication and could be used to guide the development of antiviral drugs. In July 2022, the World Health Organization declared monkeypox virus (MPXV) as a public health emergency of international concern and, as of early December 2022, more than 82,000 human monkeypox cases have been confirmed in 110 countries worldwide. New preventative and therapeutic measures against this virus are needed. In this study, Qi Peng and colleagues used cryo-electron microscopy to determine a high-resolution structure of the monkeypox virus DNA polymerase holoenzyme. According to the findings, the holoenzyme possesses an architecture that indicates a “forward sliding clamp” mechanism for DNA replication. The authors suggest that this finding could be leveraged to design anti-poxvirus drugs.