While the eradication of smallpox virus, which is a success story achieved through a common struggle in human history, eliminated a major threat, the most important advantage was that the agent (variola virus) was not of zoonotic origin. The absence of smallpox infections around the world and the termination of extensive vaccination programs have led to a decrease in global orthopoxvirus immunity day by day. The increasing number of non-immune (for poxviruses) individuals and immunocompromised (general) patients around the world brings along new risks. The predictions that monkeypox virus (MPXV), which is known to cause milder infections in humans compared to smallpox, is seen as one of the 10 infectious agents with pandemic potential, and its spread area may expand, became a reality with the virus placed on the world agenda with the last epidemic in 2022. The approval of newly developed antiviral drugs and vaccines in the last few years shows that some countries are preparing for this change. Although it has been declared by the health authorities that MPXV infections have a low rate of spread among humans and that there is no risk of a new pandemic, the fact that changes in the transmission and spread pattern of the infection carried the virus out of the African continent indicates that new endemic areas may be occur outside the continent, via transmission of the virus from domestic animals to potential reservoir animals in the wild life, continues to be a cause for concern. The spreading possibility of MPXV infections by long transmission chains in immunocompromised populations is considered as another important risk. The risk of increasing cases turning into a growing epidemic and potential biosecurity threats have also raised concerns about the production, storage, and accessibility of preventive vaccines and antiviral drugs to be used in treatment. Considering the unusual rate of human-to-human transmission observed in the recent MPXV outbreak, the spreading of the virus to multiple countries unrelated to endemic areas, and other public health risks; the importance of monitoring MPXV and other poxvirus-related human and animal infections, informing the population at risk and health care workers, and other preventive activities is clearly apparent.