Genetic discovery in inflammatory bowel disease has been incredibly successful. This provides a unique opportunity to understand what goes wrong when people develop disease, which in turn could identify better treatment targets. Yet most of this potential remains unrealised, as moving from where genetic associations lie to an understanding of how they drive disease is a formidable challenge. James Lee will discuss recent efforts to address this challenge and how his research has revealed a central orchestrator of inflammation, which could be targeted therapeutically.