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Yersinia pestis, the bacterium responsible for at least three pandemics in the past, is still a threat to modern populations. The bacterium has potential to evolve rapidly and persists in natural animal reservoirs around the globe. Epidemic diseases such as plague can dramatically alter and shape human demography, biology, and socio-cultural practices. Through the synthesis of biomolecular analyses with bioarchaeological data, researchers have begun to uncover the effects of past epidemics on modern populations and are also searching for the origins of the Y. pestis bacterium. Understanding the origins, behaviors, and consequences of diseases with epidemic potential in the past can contribute to ongoing discourse in public health, social policy, economy, and biology, as well as inspire positive changes in living populations. We review here recent literature on Y. pestis ecology and evidence of the bacteria’s evolution in prehistory before discussing ongoing research at the Hamin Neolithic settlement site that is suspected to have collapsed from an epidemic disease.