The interaction of the host with its abundant intestinal microbiota is complex and engages most of the cells in the intestinal mucosa. The inflammatory bowel diseases appear to be disorders of the host immune response to the microbiota. This is supported by data from induced gene mutations in mice and more recently by the identification of gene variants in humans that result in IBD or IBD susceptibility. These genetic studies have provided insights into the cells and molecular pathways involved in the host-microbiota dialog. This review discusses the innate, adaptive, and regulatory immune response to the microbiota in the context of the mouse and human genes that are involved in maintaining intestinal homeostasis and preventing inflammation. These data continue to support the hypothesis that inflammatory bowel disease results from a dysregulated adaptive immune response, particularly a CD4 T-cell response, to the microbiota. The microbiota itself is an active participant in these homeostatic processes. The microbiota composition is perturbed during inflammation, resulting in a dysbiosis that may induce or perpetuate inflammation. However, host genotype and the environment have a major impact on the shape of such dysbiosis, as well as upon which members of the microbiota stimulate pathogenic immune responses.