Small and intermediate conductance Ca²⁺-sensitive K⁺ channels (SKCa and IKCa, respectively) are key components in the endothelium-dependent myocyte hyperpolarization pathway in mammalian blood vessels (Edwards et al.,1998; Nature, 396, 269). Recent studies using rat mesenteric arteries are showing that endothelial cells also possess an extracellular Ca²⁺-sensing receptor (CaR) that is activated by changing the extracellular [Ca²⁺] in the range 0.5 - 5mM. Activation of the CaR leads specifically to the opening of endothelial IKCa channels and endothelial cell hyperpolarization. Using a combination of molecular approaches, microelectrode techniques and pressure myography together with ligands known to activate the CaR, the complexities of the CaR pathway in the vascular endothelium are being revealed. Molecular techniques have revealed the presence of mRNA and protein for the CaR in rat mesenteric artery and immunohistochemical staining shows that the CaR is located specifically in the endothelial layer. Activation of the CaR using endogenous ligands such as Ca²⁺ or the positive allosteric modulator, calindol, generate myocyte hyperpolarizations that can be inhibited by the IKCa blocker, TRAM-34, and concentration-dependent relaxations when vessels are mounted in a pressure myograph. Unexpectedly, sucrose-density gradient studies have revealed that IKCa channels and the CaRs are present in the non-caveolin cellular fraction rather than in the caveolin-rich fraction within which many receptors and ion channels are located (Weston et al., 2005; Circ Res., 97, 391; Absi et al., 2007; Br J Pharmacol., in press). These studies were supported by the British Heart Foundation and by the University of Aleppo, Syria.