There has been a search for more than 20 years for agents that will directly inhibit intestinal secretory mechanisms and thereby reduce stool volume in patients with high volume watery diarrhoea. Recent work has highlighted the importance of neurohumoral mechanisms in the pathogenesis of diarrhoea, notably the role of 5-hydroxytryptamine, substance P, vasoactive intestinal polypeptide and neural reflexes within the enteric nervous system. Cholera toxin and Escherichia coli enterotoxins are known to invoke these mechanisms in some diarrhoeal states. This new dimension of intestinal pathophysiology has suggested possible novel targets for anti-secretory therapy including, 5-hydroxytryptamine receptor antagonists, substance P antagonists, vasoactive intestinal polypeptide antagonists and the possibility for potentiating the pro-absorptive effects of endogenous enkephalins by use of enkephalinase inhibitors. There now seems to be a real possibility that anti-secretory therapy will become more widely available in the future.