Abstract Millions of people suffer from inflammatory diseases of the intestine, some of them potentiating gastrointestinal cancer. These gut-associated pathologies arise from imbalanced interactions between the host gut epithelia and resident or ingested microbes, interactions that are still poorly understood at the molecular level. Drosophila has been a very powerful model to study development and diseases. Its relatively simple tissue organization and sophisticated genetics are some of the advantages of using it as an experimental model to dissect gut-microbe interactions. Recent progress made in various research fields such as Drosophila microbiota composition, gut epithelium structure or gut immune reactions led us to believe that Drosophila is becoming an ad hoc model system to dissect the mechanisms that cooperate to maintain intestinal homeostasis in higher eukaryotes. It further may help us understand how an alteration of these finely tuned processes precipitates the inflammatory processes found in some inflammatory bowel diseases.