The resident macrophages of the gastrointestinal tract represent the largest population of macrophages in the human body and are usually located in the subepithelial lamina propria. This strategic location guarantees a first-line defense to the huge numbers of potentially harmful bacteria and antigenic stimuli that are present in the intestinal lumen. In non-inflamed mucosa, macrophages phagocytose and kill microbes in the absence of an inflammatory response. However, in the event of an epithelial breach and/or microbial invasion, new circulating monocytes and lymphocytes will be recruited to the damaged area of the gut, which will result in the secretion of proinflammatory mediators and engage a protective inflammatory response. Although macrophages are usually not conspicuous in normal mucosal samples of the gut, they can easily be detected when they accumulate exogenous particulate material or endogenous substances or when they become very numerous. These events will mostly occur in pathologic conditions, and this review presents an overview of the diseases which are either mediated by or affecting the resident macrophages of the gut.