Monocytes are central players in inflammation. Progress in understanding their differentiation in target tissues bears potential to manipulate their activities for therapeutic purposes. Here we propose to study the generation of intestinal macrophages (MΦs) as a paradigm, taking advantage of a unique experimental system to elucidate in vivo monocyte fates.The intestine hosts billions of bacteria that assist food uptake, but also pose a challenge, as we have to tolerate these beneficial commensals, yet rapidly mount immune responses to invading pathogens. Failure to maintain this balance causes inflammatory bowel disorders (IBD). Gut resident MΦs are key players in gut homeostasis and inflammation. Here we will study molecular parameters governing their generation from monocytes, as well as their interactions with the immediate tissue surrounding under pathological conditions. We focus on the molecular mechanisms leading to education of monocytes in small and large intestine using genome wide profiling of gene expression, chromatin state and transcription factor binding of monocytes and MΦs. Secondly, we will investigate epithelial and microflora-derived instructing cues, as well as sensory molecules on the MΦs that drive the education. Thirdly, we will study the impact of MΦs that fail to be trained and their role in the development of inflammation. Finally, we will use the insights gained to develop monocyte manipulation strategies that could aid the future development of IBD therapies.Our experimental system allows to follow the in vivo differentiation of engrafted monocytes, as physiological precursor cells, that acquire in a rapid synchronized development in the gut tissue physiologically relevant fates. Expected include (1) fundamental insight into the acquisition and maintenance of MΦ identities in a complex tissue context, (2) progress in our understanding of gut homeostasis and IBD, and (3) guiding insights for future monocyte-targeted therapy.