The metabolism of arachidonic acid by cytochrome P450 (CYP) epoxygenases generates epoxyeicosatrienoic acids (EETs) which affect numerous cellular process including Ca2+ signaling and the activity of Ca2+-dependent K+ channels. The expression of the CYP epoxygenase(s) that generate EETs in endothelial cells is not constitutive but is determined by a number of physical (fluid shear stress and cyclic stretch) and pharmacological stimuli which also affect responses attributed to an endothelium-derived hyperpolarizing factor (EDHF). This review summarizes the role played by EETs, and the enzymes that generate and metabolize them, in EDHF-mediated responses. (C) 2004 Elsevier Ltd. All rights reserved.