Intestinal epithelial cells are unique in that they represent the only host cells that are constantly interacting with a very large bacterial population in the lumen. The single monolayer of epithelial cells consists of subpopulations with distinct functions that include protection against luminal microorganisms. Although the microbial flora remains to be fully characterized, its normal relationship with the host intestinal epithelial cells appears to be predominantly symbiotic or commensal. The molecular complexity of the epithelial-microbial relationship has been shown in studies that have examined the establishment of the resident bacteria in germ-free mice. Recent work has also demonstrated the ability of resident bacteria to enhance epithelial protective responses. The mechanisms by which epithelial cells may avoid pro-inflammatory responses to resident microorganisms, while retaining the capacity to respond to pathogens, are also being characterized.