Endothelium-dependent relaxations cannot be explained only by the release of nitric oxide and/or prostacyclin. Another still unidentified substance—endothelium-derived hyperpolarizing factor (EDHF)— which hyperpolarizes the underlying vascular smooth muscle cells, may also contribute to endotheliumdependent relaxations. In human, endothelium-dependent hyperpolarizations are observed in blood vessels that exhibit endotheliumdependent relaxations partially or totally resistant to inhibitors of nitric oxide synthase and cyclooxygenase. The contribution of the EDHF response is more important in smaller than in larger arteries. The suggestion that EDHF could be a metabolite of arachidonic acid formed through cytochrome P450 is still controversial. The identification of EDHF and/or the discovery of specific inhibitors of its synthesis action will permit a better understanding of its physiological and pathophysiological role(s)...