Introduction: In 2022, the appearance of cases of Mpox outside the countries where the disease is endemic, and of some cases of human-to-human transmission, alerted the scientific community to a virus that is closely related to the smallpox virus. Mpox is a zoonosis and can be transmitted to humans. Following the eradication of smallpox in 1980 and the subsequent cessation of smallpox vaccination, it is emerging as the most important Orthopoxvirus in terms of public health impact. Methods: In outlining the current situation of Mpox in the world, the authors frame the virus responsible within a broader reflection on the Orthopoxvirus family, focusing particular attention on the Variola virus, which formerly caused millions of deaths. Discussion: Since Edward Jenner initiated the practice of vaccination, a progressive and careful vaccination campaign has led to the eradication not only of human smallpox but also of a minor form, called Alastrim, which was caused by the same virus. The mode of transmission of Mpox has been debated. At first, it seemed that the disease mainly, though not exclusively, affected men who had sex with other men. This conviction has been partially revised and the WHO recently changed the name of the disease from Monkeypox to Mpox, thereby alleviating the stigma involved. Conclusion: The recent human cases of Mpox have prompted greater surveillance and research into the biology of MPXV and other closely related poxviruses. Studies have focused on the natural history of the virus, its transmission, pathogenesis, host interactions and evolution, and on the development of drugs and vaccines to prevent its spread.