The importance of mucosal inflammation as a clinical problem is well accepted; however, the molecular and cellular signaling pathways that lead to its development remain incompletely understood. Although much attention has been placed on the role of the epithelium as a target in the mucosal inflammatory cascade, recent evidence has shed light upon the critical role that the epithelium itself, signaling in part through Toll-like receptors, may play in the initiation of a pro-inflammatory cascade in response to external stimuli. The field of mucosal inflammation research is likely to be advanced significantly through success in the following areas of study: 1) What are the relative roles of TLR signaling within the epithelium versus circulating leukocytes in the pathogenesis of mucosal inflammation? 2) What is the precise trigger for TLR signaling within the epithelium that adversely affects the host, and what are the essential roles played by mucosal TLRs in the maintenance of mucosal homeostasis? 3) Are there TLR-signaling molecular intermediates that differ between epithelial cells and leukocytes, and do such molecules confer epithelial-specific responses in the development of mucosal inflammation? 4) What regulates the interplay between the epithelium and the other cellular constituents of the mucosa, including neurons, endothelial cells, and endocrine cells during TLR activation? It is our belief that by addressing these important questions, one can be optimistic for the development of novel classes of anti-inflammatory strategies aimed specifically at the treatment of these devastating diseases of mucosal inflammation.