Functional dyspepsia (FD) is a chronic gastrointestinal disorder without a readily identifiable organic cause, resulting in bothersome upper abdominal symptoms. It is a highly prevalent disorder of which the pathophysiology remains mostly elusive, despite intensive research efforts. However, recent studies have found alterations in the microenvironment of the duodenum in patients with FD. In this review we summarize the duodenal microenvironment in homeostatic conditions and the alterations found in patients with FD, highlighting the similarities and discrepancies between different studies. The most consistent findings, being an impaired duodenal barrier and duodenal immune activation, are reviewed. We discuss the potential triggers for these observed alterations, including psychological comorbidities, luminal alterations and food related triggers. In summary, this review presents the evidence of molecular and cellular changes in patients with FD, with an impaired duodenal barrier and activated mucosal eosinophils and mast cells, challenging the notion that FD is purely functional, and offering different targets for potential future treatments.