Details of the physiology and pathophysiology of epithelial secretion in the gastrointestinal tract are becoming clear, leading to new models of the mechanisms underlying diarrhea. The enteric nervous system is a critical component of the mechanism regulating fluid secretion in the normal gut and a key element in the pathophysiology of diarrhea. Neural reflex pathways increase epithelial fluid secretion in response to several enteric pathogens of veterinary importance such as Salmonella spp., Cryptosporidium parvum, rotavirus, and Clostridium difficile. Moreover, the enteric nervous system has an important role in epithelial secretion triggered by products of activated leukocytes during inflammation. New approaches targeting the enteric nervous system show promise for the treatment of secretory diarrhea.