Intestinal inflammation has traditionally been viewed as a process in which effector immune cells cause the destruction of other mucosal cells that behave as passive bystander targets. Progress in understanding the process of intestinal inflammation has led to a much broader and more integrated picture of the various mucosal components, a picture in which cytokines, growth factors, adhesion molecules, and the process of apoptosis act as functional mediators. Essentially all cellular and acellular components can exert immunelike activities, modifying the classical concept of selected immune cells acting on all other cells that has been the dogma of immunologically mediated tissue damage for decades. The existence of specialized communication pathways between epithelial cells and T cells is well documented, including abnormal epithelial cell-mediated T cell activation during inflammation. Mesenchymal cells contribute to fibrosis in the inflamed gut but are also responsible for retention and survival of leukocytes in the mucosa. In chronically inflamed intestine the local microvasculature displays leukocyte hyperadhesiveness, a phenomenon that probably contributes to persistence of inflammation. The extracellular matrix regulates the number, location, and activation of leukocytes, while metalloproteinases regulate the quantity and type of deposited matrix proteins. This evidence from the intestinal system, consolidated with the use of data from other organs and systems, reveals a rich network of reciprocal and finely orchestrated interactions among immune, epithelial, endothelial, mesenchymal, and nerve cells and the extracellular matrix. Although these interactions occur under normal conditions, the dysfunction of any component of this highly integrated mucosal system may lead to a disruption in communication and result in pathological inflammation.