Ancient DNA analysis has uncovered that the plague, infamous for its devastating impact during the 14th century Black Death, continued to affect Europe for more than 400 years. A study led by researchers at the University of Tartu examined DNA from the plague bacterium, Yersinia pestis, preserved in human remains found at 11 archaeological sites across Estonia, Russia, England, the Netherlands, and Switzerland. These remains date from the 14th to the 18th centuries, covering most of the period known as the Second Plague Pandemic, which followed the initial Black Death outbreak. The genetic evidence challenges the idea that the plague simply survived in one location and spread outward from a single point. Instead, the disease repeatedly emerged in different parts of Europe over several centuries, possibly creating multiple new reservoirs where the bacterium could persist. Estonia, in particular, was repeatedly affected by plague during this time. The country’s extensive trade and travel connections with other parts of Europe likely played a role in the movement of the disease across long distances. One of the most notable patterns occurred between 1450 and 1500, when plague lineages experienced a major expansion and split into three significant branches. These branches may have contributed to the establishment of new reservoirs of Yersinia pestis in wild rodent populations, which are natural hosts for the bacterium. Climate changes during this time, such as the Great Renaissance Drought, may have influenced this expansion, as changes in climate can significantly affect rodent populations and, in turn, the spread of the disease. A major challenge in studying historical pandemics is determining the exact timing of ancient infections. To address this, the researchers developed a method to refine the dating of ancient plague genomes by examining their placement on the bacterium’s evolutionary tree. This allowed them to align ancient infections with more precise historical timelines and link them to specific plague outbreaks recorded in historical documents. The genetic record also highlights how human activity influenced the spread of plague. Newly analyzed genomes provide evidence connecting outbreaks to major conflicts such as the Thirty Years' War (1618-1648) and the Great Northern War (around 1700-1721). Armies, displaced civilians, refugees, and traders often traveled along the same routes, creating conditions that facilitated the movement of disease between regions. For example, during the 1710 siege of Tallinn, plague killed both Swedish and Russian soldiers and local civilians. These findings reveal a disease that continuously crossed borders, evolved into new forms, followed human movement, and shaped Europe for centuries after the Black Death had ended. Understanding how the plague became established after the initial outbreak, remained present for so long, and eventually disappeared from Europe could offer important insights into the long-term behavior of infectious diseases.