Like many eicosanoids, epoxyeicosatrienoic acids (EETs) have multiple biological functions, including reduction of blood pressure, inflammation, and atherosclerosis in multiple species. Hydration of EETs by the soluble epoxide hydrolase (sEH) is the major route of their degradation to the less bioactive diols. Inhibition of the sEH stabilizes EETs, thus, enhancing the beneficial effects of EETs. Human data show an association of sEH (Ephx2) gene polymorphisms with increased risk of atherosclerosis and cardiovascular diseases. These data suggest a potential therapeutic effect of sEH inhibitors (sEHI) in the treatment of atherosclerosis. Indeed, two laboratories reported independently that using different sEHIs in apolipoprotein E-deficient mice significantly attenuated atherosclerosis development and aneurysm formation. The antiatherosclerotic effects of sEHI are correlated with elevation in EET levels and associated with reduction of low-density lipoprotein and elevation of high-density lipoprotein cholesterols, as well as attenuation of expression of proinflammatory genes and proteins. In addition, the antihypertensive effects and improvement of endothelial function also contribute to the mechanism of the antiatherosclerotic effects of sEHI. The broad spectrum of biological action of EETs and sEHIs with multiple biological beneficial actions provides a promising new class of therapeutics for atherosclerosis and other cardiovascular diseases.