This review presents recent findings regarding the physiological and pathophysiological extra- and intracellular mechanisms of secretory diarrhoea. Putative interventions directed towards counteracting the mechanisms causing fluid loss, especially in relation to the enteric nervous system, intracellular mediators, and localization of fluid and electrolyte transport, are discussed. The enteric nervous system regulates the complex process of transmural fluid and electrolyte transport by controlling the function of the mucosa, the motility, and the microcirculation in both health and disease. Most of the processes, leading to secretory diarrhoea, involve activation of the enteric nervous system, with local release of neurotransmitters and other endogenous effectors, which induce chloride secretion. A new therapeutic approach is based on stimulation of absorption and inhibition of secretion by using receptor agonists and antagonists, and modulators of intracellular signal transduction. A physio-pharmacological review of serotonin and the antisecretory factor as modulators of intestinal fluid and electrolyte transport is given.