Some ideas return after the briefest of exiles: reductionism is back in vogue. Existential questions – about who we are, about our origins and future, about what is valuable – no longer require difficult soul searching, especially when straightforward answers are expected from the neurosciences. History is being rewritten with the brain as its centrepiece; the search for great men and big ideas of the past begins again. William Cullen (1710–90), whose work on neurosis was once part of the history of psychoanalysis, is now well placed to become part of such a neuro-history. This article attempts to subvert this process, by rebuilding the original meaning of neurosis through Cullen’s physiological and medical works, in comparison with his predecessor, Robert Whytt (1714–66), and illustrating this meaning using one particular neurosis: hypochondriasis. The result is a more complicated version of neurosis which, importantly, carries significant insights into the nature and practice of medicine. Moreover, this article examines how Cullen’s standing fell in the 1820s as British physicians and surgeons turned to an idea which promised to reform medicine: pathological anatomy. When these hopes faded, Cullen became a figure obsessed with the nerves. This image has survived to the present, a blank canvas onto which any theory can be projected. It also values precisely what Cullen warned against: simplistic explanations of the body and disease, and unthinking confidence in the next big idea or silver bullet. Neurosis was not simply a nervous ailment, but it is a warning against reductionism in history making.