This case study explores the etiological mystery of the English sweating sickness (ESS) that threatened Europeans during the years 1485-1551 before abruptly vanishing. Numerous pathogens have been proposed to explain ESS, but none are completely satisfactory (e.g., hantavirus, anthrax, ergot, arbovirus, influenza, relapsing fever, etc.). Students assume the role of the royal physician to the King of England and investigate the genesis, pattern of spread, similarities, and differences of major disease outbreaks. In this flipped classroom design, students complete the first two sections of the case before class by reviewing relevant literature and selected videos. In class, students work in groups to discuss a list of eleven symptoms and then compare the list to the symptoms for ten different suspected diseases. The case concludes with student groups presenting a synopsis of their assigned diseases and analyzing which had the most symptoms in common with ESS to hypothesize a possible culprit. The case is suitable for undergraduate students enrolled in second-semester biology, microbiology, virology, physiology, epidemiology, seminar, history of science, or related courses.