The epithelial lining of the intestine forms a barrier that separates the intestinal lumen from the host's internal milieu and is critical for fluid and electrolyte secretion and nutrient absorption. In the early 1990s, my laboratory discovered that intestinal epithelial cells could alter their phenotype and produce proinflammatory chemokines and cytokines when stimulated by pathogenic enteric luminal microbes or proinflammatory agonists produced by cells in the underlying mucosa. It is now well accepted that intestinal epithelial cells can be induced to express and secrete specific arrays of cytokines, chemokines, and antimicrobial defense molecules. The coordinated release of molecules by intestinal epithelial cells is crucial for activating intestinal mucosal inflammatory responses as well as mucosal innate and adaptive immune responses. More recent studies have focused on the intestinal epithelial signaling pathways that culminate in immune activation as well as the role of these pathways in host defense, mucosal injury, mucosal wound healing, and tumorigenesis. The emerging picture indicates that intestinal epithelial cells represent an integral component of a highly regulated communications network that can transmit essential signals to cells in the underlying intestinal mucosa, and that intestinal epithelial cells, in turn, serve as targets of mucosal mediators. These signals are essential for maintaining intestinal mucosal defense and homeostasis.