The cytochrome (CYP) P450 epoxygenase pathway catalyzes the epoxidation of arachidonic acids to epoxyeicosatrienoic acids, which are subsequently hydrolyzed to less active dihydroxyeicosatrienoic acids by soluble epoxide hydrolase. Numerous preclinical studies have demonstrated that CYP-derived epoxyeicosatrienoic acids possess potent vasodilatory and anti-inflammatory properties in the cardiovascular system. In humans, functionally relevant polymorphisms, which may significantly modulate epoxyeicosatrienoic acid levels in vivo, have been identified in the genes encoding CYP2J2, CYP2C8, CYP2C9 and soluble epoxide hydrolase. Initial epidemiologic studies have demonstrated that genetic variation in the CYP epoxygenase pathway significantly modifies cardiovascular disease risk at the population level in humans, providing support for the hypothesis that modulation of this pathway may represent a novel approach to the prevention and treatment of cardiovascular disease. Future studies in humans validating these relationships and characterizing the underlying mechanisms will be necessary to fully understand the functional role of the CYP epoxygenase pathway in cardiovascular disease.