The emergence of a gastrointestinal tract within the body cavity is one of the major innovations in animal evolution allowing the transition from an intra- to an extracellular mode of digestion. With this emergence came the opportunity for infectious agents to exploit this intestinal ecosystem for their own transmission. Gut-bearing organisms therefore evolved complex mechanisms to defend themselves against these agents, making them “gut immunocompetent”. This involved a process of continuous adaptation and counter-adaptation in the two competing species, host and pathogen, rendering gut immunocompetence a complex trait with a large genetic component. Important progress has been made to elucidate the biological processes underlying gut immunocompetence, revealing an intricate interplay between immunological, stress, and neuronal signaling as well as gut regeneration and wound repair. However, how this multilayered regulatory network is encoded at the molecular level and how genetic variation of the host species contributes to this trait is still poorly understood. Here, we propose a global and interdisciplinary study, combining regulatory genomics and bioinformatics, to elucidate the genetic and molecular mechanisms underlying gut immunocompetence and its variation in Drosophila melanogaster. By determining the regulatory targets of transcription factors involved in the interplay between the immune response pathways, relating them to known physiological outputs, and computationally mining the genetic variants that may lie at the basis of the observed phenotypic variation, we expect to elucidate the regulatory networks mediating gut immunocompetence and how they are impacted by genomic variation. This would not only constitute a breakthrough in the field of innate immunity, but a sound foundation for understanding the molecular driving forces that impact genetic variation of a complex trait in general.