Polymorphisms associated with two genes in the autophagy pathway, ATG16L1 and IRGM1, have been implicated in susceptibility to Crohn’s disease, an idiopathic inflammatory disease typically involving the gastrointestinal tract. The intestinal mucosa is a site of careful immune regulation where the epithelium and immune cells encounter pathogens as well as a robust and diverse population of indigenous microbes that are predominately bacteria. Since the role of autophagy in immunity is broad and expanding, it is unclear which downstream functions of autophagy and which cell types are the key factors in Crohn’s disease susceptibility. This chapter reviews the recent literature on the roles of ATG16L1 and IRGM1 in the autophagy pathway, inflammation, antimicrobial immunity, and the biology of the intestine, and discusses how these genes may contribute to Crohn’s disease pathogenesis.