Functional gastrointestinal disorders-recently renamed into disorders of gut-brain interaction-such as irritable bowel syndrome and functional dyspepsia are highly prevalent conditions with bothersome abdominal symptoms in the absence of structural abnormalities. While traditionally considered as motility disorders or even psychosomatic conditions, our understanding of the pathophysiology has evolved significantly over the last two decades. Initial observations of subtle mucosal infiltration with immune cells, especially mast cells and eosinophils, are since recently being backed up by mechanistic evidence demonstrating increased release of nociceptive mediators by immune cells and the intestinal epithelium. These mediators can activate sensitised neurons leading to visceral hypersensitivity with bothersome symptoms. The interaction between immune activation and an impaired barrier function of the gut is most likely a bidirectional one with alterations in the microbiota, psychological stress and food components as upstream players in the pathophysiology. Only few immune-targeting treatments are currently available, but an improved understanding through a multidisciplinary scientific approach will hopefully identify novel, more precise treatment targets with ultimately better outcomes.