The intestine is the most densely colonized site in both mice and man. Recent data suggest that the intestinal flora is, in part, controlled by antimicrobial substances secreted by the intestinal epithelium. The defense system of the small intestine includes a protective mucus layer, a high turnover of epithelial cells, and a regulated secretion of effector molecules, notably antimicrobial peptides. Human and mouse small intestines share many similarities in their intestinal defense micro-organization, including the secretion of the well-known α-defensins. Mice, however, produce an additional unique antimicrobial peptide family, the CRS (cryptdin-related sequences)-peptides, not found in man. This review comprises a detailed presentation of the peptide-based defense of the gut, with specific emphasis on the CRS-peptide family. The first part presents the current knowledge of the CRS-peptide family's biochemical characteristics and nomenclature, and the second part is devoted to the possible role of this family in the homeostasis of the gut.