Cultures of Plague discloses a new chapter in the history of medicine. Neither the plague nor the ideas it stimulated were static, fixed in a timeless Galenic vacuum over five centuries, as historians and scientists commonly assume. As plague evolved in its pathology, modes of transmission, and the social characteristics of its victims, so did medical thinking about it. With over 600 plague imprints of the sixteenth century this study highlights the century's most feared and devastating epidemic that threatened Italy top to toe from 1575 to 1578, unleashing an avalanche of plague writing. From erudite definitions, remote causes, cures and recipes, physicians now directed their plague writings to the prince and discovered their most ‘valiant remedies' in public health: strict segregation of the healthy and ill, cleaning streets, latrines, and addressing the long‐term causes of plague—poverty. Those outside the medical profession joined the chorus. Relying on health board statistics and dramatized with eyewitness descriptions of bizarre happenings, human misery, and suffering, they created the structure for the plague classics of the eighteenth century and by tracking the contagion's complex and crooked paths anticipated trends of nineteenth‐century epidemiology. In the heartland of Counter‐Reformation Italy, physicians, along with those outside the profession, questioned the foundations of Galenic and Renaissance medicine, even the role of God. Such developments did not need to await the Protestant‐Paracelsian alliance of seventeenth‐century northern Europe. Instead, creative forces planted by the pandemic of 1575–8 sowed seeds of doubt and unveiled new concerns and ideas within that supposedly most conservative form of medical writing, the plague tract.