Endothelium-derived mediators, such as nitric oxide, prostacyclin and the putative endothelium-derived hyperpolarizing factor (EDHF), play an important role in mediating relaxation of blood vessels. Should EDHF exist then it would be an endogenous activator of potassium channels and this offers the prospect of developing mimetcs. Although the nature of EDHF and, indeed, the very existence of EDHF remains unclear, the changes that occur in endothelium function in disease states indicate that EDHF is not simply a backup for NO. There is considerable evidence suggesting that vasoactive substances exert regional-dependent vascular effects. However, the heterogeneity of the pharmacological properties of EDHF has given rise to the hypothesis that multiple EDHFs may exist and, if this is the case, the exciting prospect of developing novel vascular bed-dependent therapeutic agents selectively modulating blood flow to a specific organ. Conversely, selective inhibitors of EDHF may be useful in certain disease states.