Inflammatory bowel disease appears to result from an abnormal host immune response to the intestinal microbiota. Experimental models have allowed the dissection of the complex dialog between the host and its microbiota. Through genetic manipulation of the host genome the immune compartments, cells, molecules, and genes that are critical for maintenance of intestinal homeostasis are being identified. Genetic association studies in humans have identified over 100 susceptibility loci. Although there is remarkable coherence between the experimental model and the human genetic data, a full understanding of the mechanisms involved in genetic susceptibility to IBD and of gene-gene and gene-environmental interactions will require a "next generation" of experimental models.