The gut is the major interface between microbes and their animal hosts and constitutes the main entry route for pathogens. As a consequence gut cells must be armed with efficient immune defenses to combat invasion and colonisation by pathogens. However, the gut also harbors a flora of commensal bacteria, with potentially beneficial effects for the host, which must be tolerated without a chronic, and harmful, immune response. In recent years Drosophila has emerged as a powerful model to dissect host-pathogen interactions, leading to the paradigm of antimicrobial peptide regulation by the Toll and Imd signaling pathways. The strength of this model derives from the availability of powerful and cost effective genetic and genomic tools as well as the high degree of similarities to vertebrate innate immunity. However, in spite of growing interest in gut mucosal immunity generally, very little is known about the immune response of the Drosophila gut. Using powerful new tools and those developed in the study of the systemic response, we propose to raise our understanding of Drosophila gut immunity to the same level as that of systemic immunity within the next five years. This project will involve integrated approaches to dissect not only the gut immune response but also gut homeostasis in the presence of commensal microbiota, as well as strategies used by entomopathogens to circumvent these defenses. We believe that the fundamental knowledge generated on Drosophila gut immunity will serve as a paradigm of epithelial immune reactivity and have a wider impact on our comprehension of animal defense mechanisms.