Ottoman perceptions of and responses to epidemic diseases changed dramatically in the sixteenth century. Until that time, plagues were viewed in mostly supernatural-apocalyptic terms. However, with the development of a new body of knowledge and interpretations, plagues came to be seen in a more naturalistic-medical framework. Moreover, this new approach was used for justifying administrative and legal practices implemented for the control of epidemic outbreaks. This article explores the historical context in which this paradigmatic change took place, with a view to establishing the complex relationship between the expanding powers of early modern state governance and the discourses of plagues maintained by the Ottoman society.