After blockade of both NO and PGI2, a substantial degree of endothelium-dependent vasodilatation is still observed and is attributed to EDHF. Despite almost two decades of research and debate, the exact nature of EDHF and its mechanism of action remain unclear. Consistently, EDHF's role as a vasodilator is most prominent in the smaller resistance arteries that are responsible for the control of systemic blood pressure and local organ perfusion. As well as its involvement in physiological processes, alterations in EDHF activity may contribute to the vascular effects of the myriad of conditions either caused by, or resulting in, endothelial dysfunction. However, the lack of understanding of EDHF has precluded its direct manipulation as a specific therapeutic target.