Interferon (IFN) family cytokines stimulate a broad group of genes known as interferon stimulated gene (ISGs). The primary function of ISGs is to provide antiviral host defense. IFN-α and IFN-β signal through IFN-α receptor (IFNAR) whereas IFN-λ signals through IFN-λ receptor (IFNLR). IFNAR is expressed by many cell types, but IFNLR is primarily expressed by epithelial cells in barrier tissues. However, unlike most epithelial barriers that respond to both IFN-λ and IFN-α/β, intestinal epithelial cells (IECs) preferentially respond to IFN-λ and are hyporesponsive to IFN-α/β. As such, IFN-λ has a dominant role in protecting IECs from enteric viruses. The physiological rationale for this selective responsiveness by IECs is poorly understood. Furthermore, the interactions of IFN-λ signaling in IECs with the environmental context of bacterial microbiota have not been determined. In this dissertation, I describe the consequences and contexts surrounding the IFN-λ response by IECs.