Monkeypox is a zoonotic disease caused by infection with the monkeypox virus (MPXV), a member of the Orthopoxvirus genus. MPXV most commonly circulates in Central and West Africa, but an outbreak in 2022 has seen dozens of non-endemic countries reporting hundreds of monkeypox cases, often without known epidemiological links to Africa. Gigante et al. identified two distinct genomic lineages of MPXV that are found among nine monkeypox cases from 2021 and 2022 in the USA: a predominant 2022 variant termed B.1 and a minor variant termed A.2. Genetic analysis of these two variants revealed a marked preponderance of guanine-to-adenine modifications within motifs recognized by the apolipoprotein B editing complex (APOBEC3) cytosine deaminase, a host anti-viral defence protein that catalyses single base pair mutations. These findings indicate that MPXV evolution might be driven by APOBEC3 activity, a previously unrecognized or unappreciated mechanism of poxvirus mutation.