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Recent biomolecular evidence has proven that Yersinia pestis, the pathogen that causes bubonic plague, was infecting human hosts in Eurasia as early as the Bronze Age, far earlier than previously believed. It remains an open question, however, whether bubonic plague was affecting Mediterranean populations of classical antiquity. This article evaluates the textual evidence for bubonic plague in classical antiquity from medical sources and discusses methodologies for “retrospective diagnosis” in light of new developments in microbiology. A close study of Greek medical texts suggests that bubonic plague was unfamiliar to medical writers until sometime before the second century AD, when sources cited by Rufus of Ephesus report a disease that resembles bubonic plague. Rufus of Ephesus describes this disease around AD 100, and Aretaeus (fl. ca. AD 50 or 150) appears to describe the same disease as well. Intriguingly, the disease then disappears from our sources until late antiquity.