IL-17A/F signaling through the IL-17RA/RC receptor complex plays a vital role in immunity and inflammation. The expression of IL-17RA/RC by diverse intestinal epithelial cell types including Paneth cells and the observation that therapies neutralizing IL-17A or IL-17RA in Crohn’s disease (CD) patients induce adverse events suggest essential homeostatic functions of this cytokine. Paneth cells and their antimicrobial products (a-defensins, lysozyme etc.) play a critical role in mediating small intestinal host defense under homeostatic conditions as well as after injury or infection, and their dysregulation constitutes a pathogenic factor for CD.