In this article I present a socio-historical analysis of the definition and diagnosis of one particular genetic disease – cystic fibrosis (CF) – in an effort the better to understand its social context both before and after the advent of molecular genetics. I begin my analysis with some background on the history of CF, before moving on to consider the emergence of the notion of classic CF, the development of the sweat test, early approaches to mild or variant forms of CF, the concept of CF as a genetic disease, the concept of CF as a collection of related disorders, and developments in the understanding and diagnosis of CF which came about in the wake of molecular genetics. I highlight a range of technological, professional and patient developments and how these stimulated new research, typologies and clinical tools. I also consider how different notions of CF were mobilised, either to support or undermine a particular approach to diagnosis or treatment, and consider how the dynamic and contextual characteristics of CF were accounted for by scientists and clinicians with an interest in CF. I end by discussing the implications of my analysis for the contemporary sociology of genetics, and related studies in the sociology of medicine more generally.