For many years, the endothelium was viewed as a simple and inert barrier separating the blood from pro-aggregatory components of the sub-intima. This changed dramatically around thirty years ago, such that the endothelium is now viewed as a key endocrine organ and central to cardiovascular function. This shift followed the discovery that endothelial cells elaborate the vasodilators prostacyclin and nitric oxide. Key to these discoveries was the use of the pharmacological technique of bioassay, a technique that subsequently enabled the discovery of endothelium-derived hyperpolarizing factor (EDHF), a mechanism that is particularly important in small arteries and thus has a significant influence on blood pressure and flow distribution. The idea of EDHF as a diffusible factor causing smooth muscle hyperpolarization (and thus vasodilatation) has unraveled to reveal a complex pathway activated by the opening two Ca²⁺-sensitive K-channels, K_Ca2.3 and K_Ca3.1, that are both restricted to the endothelium. Combined application of apamin and charybdotoxin blocked EDHF responses, revealing the critical role played by these channels, since iberiotoxin was unable to substitute for charybdotoxin. Having discovered these channels are both crucial for EDHF and restricted to the endothelium, we showed the channels are arranged in discrete endothelial microdomains, particularly within projections toward the adjacent smooth muscle and close to interendothelial gap junctions. Activation of these K_Ca channels hyperpolarizes the endothelial cells, and K⁺ effluxing through them can act as a diffusible 'EDHF' by stimulating Na⁺/K⁺-ATPase and inwardly-rectifying K-channels. In parallel, hyperpolarizing current spreads from the endothelium to the smooth muscle through myoendothelial gap junctions on the endothelial projections. The resulting radial hyperpolarization mobilized by EDHF is complemented by spread of hyperpolarization along arteries and arterioles, affecting distant dilatation dependent upon the endothelium. Thus, the complexity of the endothelium still continues to unravel and provides considerable potential for novel therapeutic approaches to modulate blood pressure.