Epoxyeicosatrienoic acids (EETs) are generated from arachidonic acid by cytochrome P450 (CYP) epoxygenases. The expression of CYP epoxygenases in endothelial cells is determined by a number of physical (fluid shear stress and cyclic stretch) and pharmacological stimuli as well as by hypoxia. The activation of CYP epoxygenases in endothelial cells is an important step in the nitric oxide and prostacyclin (PGI2)-independent vasodilatation of several vascular beds and EETs have been identified as endothelium-derived hyperpolarizing factors (EDHFs). However, in addition to regulating vascular tone, EETs modulate several signaling cascades and affect cell proliferation, cell migration, and angiogenesis. Signaling molecules modulated by EETs include tyrosine kinases and phosphatases, mitogen-activated protein kinases, protein kinase A (PKA), cyclooxygenase (COX)-2, and several transcription factors. This review summarizes the role of CYP-derived EETs in cell signaling and focuses particularly on their role as intracellular amplifiers of endothelial cell hyperpolarization as well as in cell proliferation and angiogenesis. The angiogenic properties of CYP epoxygenases and CYP-derived EETs implicate that these enzymes may well be accessible targets for anti-angiogenic as well as angiogenic therapies.