In northern Chile, DNA recovered from two naturally mummified Indigenous individuals has provided the first known ancient smallpox genomes in the Americas. This significant discovery fills a gap in the evolutionary history of the variola virus, supporting historical accounts that suggest smallpox was introduced to the Americas during European colonization. The research team, led by doctoral student Bruno Romero González from Trinity College Dublin, initially aimed to study the ancestry and population history of the region's Indigenous people. However, upon screening the samples for ancient pathogens, they uncovered genomic evidence of a smallpox strain circulating in colonial Chile. The analysis was conducted using advanced software that identifies genetic signatures of ancient bacteria and viruses. The findings reveal that while only two genomes were analyzed, they represent a crucial addition to the historical variola virus genome database. Ana Duggan, acting chief of computational and operational genomics at the Public Health Agency of Canada's National Microbiology Laboratory, emphasized the importance of this discovery in understanding the historical context of smallpox epidemics recorded by colonial chroniclers. These accounts often lacked the ability to identify the specific pathogens responsible for the outbreaks. The research highlights the evolutionary trajectory of the variola virus, showing that it accumulated mutations at a steady pace for centuries before entering a period of slower change coinciding with European colonial expansion. This period of reduced mutation rates may have been influenced by the interconnectedness of populations and repeated epidemics, which favored a virus already well adapted to human hosts. The pace of evolution increased again around the time widespread vaccination began, suggesting a potential link between vaccination efforts and viral evolution. The collaboration between Romero González and de la Fuente Castro's research team exemplifies the merging of expertise in human history and pathogen research. Their findings not only provide genomic evidence of smallpox in Chile but also underscore the importance of interdisciplinary approaches in uncovering historical narratives. This research opens new avenues for understanding the impact of infectious diseases on Indigenous populations during the colonial period and highlights the need for further studies to explore the full extent of smallpox's influence in the Americas.