Abstract An unintended consequence of smallpox eradication and ending the smallpox vaccination campaign has been to render the global human population immunologically naïve to orthopoxvirus infection for the first time in history. This has occurred at a time when the majority of people worldwide live in high population densities in cities and when connectivity across the world has never been higher, both of which facilitate the emergence and spread of infectious diseases. It is not surprising, therefore, that novel zoonotic orthopoxvirus infections have been increasing in recent years, or that an international outbreak of human monkeypox disease has occurred. A One Health approach, including consideration of land-use change and the bushmeat and exotic pet trades, is required to prevent opportunities for the emergence of monkeypox, or diseases cause by other orthopoxviruses, and for a rapid and effective response to any outbreaks in order to limit their spread. One Health Impact Statement The current global outbreak of monkeypox is yet another warning for the adoption of a preventative, One Health, approach to minimise the risk of future emergence of known and unknown zoonotic pathogens. This includes the need to consider the roles, and to mitigate the impacts, of land-use change and the bushmeat and exotic pet trades in order to prevent opportunities for the emergence of monkeypox virus, or other orthopoxviruses, and for a rapid and effective response to any outbreaks in order to limit their spread. As of 9 September 2022, there have been 56,098 confirmed cases of monkeypox in people in 96 countries since an initial case was confirmed in the UK on 7 May (CDC, 2022). However, this does not include infections in Central and West Africa where the infection is endemic and where human cases of the disease have been escalating dramatically in recent years following smallpox eradication ( Tasamba, 2022 ). Monkeypox virus (MPV), the causative agent of monkeypox, is an orthopoxvirus (OPV) closely related to smallpox virus. Following a global vaccination campaign, the World Health Assembly confirmed the eradication of smallpox in 1980, after which vaccination against this disease was ended. During the following 40 years, therefore, and for the first time in history, the global human population has become immunologically naïve to OPVs ( Dye and Kraemer, 2022 ). This has created a gaping ecological niche that is open to exploitation by a new OPV. It is perhaps not surprising, therefore, that zoonotic infections with at least two previously unknown OPVs have emerged in recent years: Akhmeta pox and Alaska pox ( Vora et al ., 2015 ; Springer et al ., 2017 ). Monkeypox virus is also a zoonotic OPV and, although recognized for many years as a public health threat in waiting subsequent to the decline of smallpox vaccination ( Heymann et al ., 1998 ), monkeypox has remained a neglected disease ( Di Giulio and Eckburg, 2004 ; Parker et al ., 2007 ), which is only now receiving attention following its spread to high-income countries.