Yersinia pestis has co-existed with humans for millennia is regarded as the principal cause of at least three plague pandemics, one being the Black Death (~ 1346–1353 in Europe). Subsequent periodic outbreaks affected Eurasian populations for centuries. This model provides clues regarding disease emergence, resurgence, susceptibility and local eradication. The Black Death killed tens of millions of people in Europe alone, and precipitated important demographic, economic and socio-political changes. Ancient biomolecular evidence confirms Y. pestis as the cause of Black Death and evidence implicates this bacterium in human infections dating to the Neolithic. Today, plague has a near-global distribution, with natural foci on nearly every continent. The 2017 Madagascar plague outbreak killed hundreds and showed an unexpectedly high proportion of pneumonic cases (the most fatal form of the disease). We must clarify how plague has repeatedly affected human populations, why its epidemiology has apparently changed since the medieval period and improve our understanding of how humans and pathogens coevolve. This chapter explores palaeodemographic and palaeoepidemiological research on medieval burials, including plague victims. Medieval epidemic patterns of mortality can provide clues about those who died, and those who survived. It explores the genetic relationships of Y. pestis strains from a number of post-Black Death epidemic burials to clarify distribution and local evolution of plague, and competing hypotheses of past local plague reservoirs in Europe/its environs.