Chapter 1 tracks frenzy’s trajectory as a medical diagnosis between 1500 and 1700. It offers an introduction to frenzy as it was understood by eight medical practitioners, four of whom came of age in a time of relative stability in English medicine (1560–1640) and four in a time of rapid change (1640–1700). It shows how, from the mid seventeenth century, the old humoral definition of frenzy was altered to fit new medical philosophies – chemical, mechanistic, and corpuscular – and new models of human physiology. Tracing the contours of the disease over two centuries, it highlights points of continuity as well as change. Throughout this period, it argues, theorists from diverse schools explained frenzy’s effects with reference both to the solid structures of the body and the fluids which flowed through them. This chapter argues that it was the devastating effects of brain disease which galvanized medical theorists to seek to explain disorders of the mind as disruptions of material ‘animal spirits’.