Orthopoxvirus (OPV) infections have been present in human life for hundreds of years. It is known that Variola virus (VARV) killed over 300 million people in the past; however, it had an end thanks to the physician Edward Jenner (who developed the first vaccine in history) and also thanks to a massive vaccination program in the 20th century all over the world. Although the first vaccine was created using the Cowpox virus (CPXV), it turned out later that the Vaccinia virus was the one used during the vaccination program. VACV is the etiological agent of bovine vaccinia (BV), a zoonotic disease that has emerged in Brazil and South America in the last 20 years. BV has a great impact on local dairy economies and is also a burden to public health. In this review, we described the main events related to VACV and BV emergence in Brazil and South America, the increase of related scientific studies, and the issues that science, human and animal medicine are going to face if we do not be on guard to this virus and its disease.