Recent knowledge of neuro-endocrine-immune communication in the intestinal mucosa has provided a new paradigm for the pathophysiology of diarrheal disease that will significantly alter and advance therapeutic strategies. Mast cells, enteroendocrine cells and phagocytes are the proximate mediators of signalling cascades activated by parasitic nematodes and food allergens, enterotoxigenic bacteria, and at least some of the invasive pathogens, respectively. These proximate, trigger cells give rise to products that affect epithelial function directly, or indirectly through stimulation of prostaglandin production by mesenchymal cells, and enteric nerve stimulation, which can markedly amplify the initial stimulus. The enteric nervous system in fact may mediate the majority of the secretory response induced by enterotoxins or phagocytes. The signalling network mediated by cells in the lamina propria provides new points of control for pharmacological therapy.