Although variola virus (VARV) has been eradicated through widespread vaccination, other pathogenic for humans circulate in nature. Recently, new , including some able to infect humans, have been found and their complete genomes have been sequenced. Questions about the mutation rate and the emergence of new threats to humankind as a result of the evolution of circulating remain open. Based on contemporary data on ancient VARV DNA and DNA of new species, an analysis of the molecular evolution of was carried out and the timescale of their emergence was estimated. It was calculated that the of the Old and New Worlds separated approximately 40,000 years ago; the recently discovered Akhmeta virus and Alaskapox virus separated from other approximately 10,000-20,000 years ago; the rest of modern orthopoxvirus species originated from 1700 to 6000 years ago, with the exception of VARV, which emerged in approximately 300 AD. Later, there was a separation of genetic variants of some species, so the monkeypox virus West African subtype originated approximately 600 years ago, and the VARV minor alastrim subtype emerged approximately 300 years ago.