Inflammatory bowel disease (IBD) is a family of conditions characterized by chronic, relapsing inflammation of the gastrointestinal tract. IBD afflicts over 3 million adults in the United States and shows increasing prevalence in the Westernized world. Current IBD treatments center on modulation of the damaging inflammatory response and carry risks such as immunosuppression, while the development of more effective treatments is hampered by our poor understanding of the molecular mechanisms of IBD pathogenesis. Previous genome-wide association studies (GWAS) have demonstrated that gene variants linked to the cellular response to microorganisms are most strongly associated with an increased risk of IBD. These studies are supported by mechanistic work demonstrating that IBD-associated polymorphisms compromise the intestine's anti-microbial defense. In this review, we summarize the current knowledge regarding IBD as a disease of defects in host-microbe interactions and discuss potential avenues for targeting this mechanism for future therapeutic development.