Intestinal epithelial layer is an important barrier against antigen invasion. In addition to its barrier function, the immunomodulatory role of intestinal epithelium is attracting considerable attention. The intestinal epithelium may influence underlying immune cells including dendritic cells and lymphocytes and promote tolerogenic and regulatory responses in health. Breakdown of such regulatory influences may result in uncontrolled inflammation and tissue damage. The molecules mediating such regulation derived from intestinal epithelium and their interaction with immune cells may provide novel targets and therapeutic molecules that have translational potential in intestinal inflammation. Understanding the cross-talk between intestinal epithelium and immune cells has progressed from in vitro co-culture models to epithelial cell conditional knockout models.