In the late eighties, several studies revealed the existence of a third vasodilating factor next to nitric oxide (NO) and prostacyclin (PGI2). As the action of this third factor is closely related to smooth muscle hyperpolarization, this factor was termed endothelium-derived hyperpolarizing factor (EDHF). The story of its investigation is a confusing one and several different candidate molecules and pathways have been proposed to account for the EDHF phenomenon. Major candidate molecules/mediators of EDHF signalling are K+, electrical coupling through gap junctions, cytochrome P450 metabolites, and endothelial small- and intermediate Ca2+-activated K+ channels (SK(Ca) and IK(Ca)). In this mini review, we wish to convey that EDHF is as powerful as NO and PGI2 in terms of blood pressure regulation and that deficiency in EDHF signalling contribute to several cardiovascular pathologies such as hypertension, chronic renal failure, and diabetes. In addition, we focus on recent insight into the EDHF phenomenon provided by novel genetic animal models, such as mice deficient of either endothelial SK(Ca) or IK(Ca) and the impact of channel deficiency on endothelial function, EDHF signalling, and arterial blood pressure.