Diets rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs) such as alpha-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid are associated with decreased incidence and severity of cardiovascular disease (CVD). At least some of the beneficial effects of these dietary fatty acids are mediated by metabolites such as prostaglandins, leukotrienes, thromboxanes, and resolvins. The effects of n-3 PUFAs often differ from those of other fatty acids with very similar structures, such as linoleic acid and arachidonic acid (n-6 PUFAs) and their corresponding metabolites. This article reviews the evidence that specific receptors exist for fatty acids or their metabolites that are able to regulate gene expression and coordinately affect metabolic or signaling pathways associated with CVD. Four nuclear receptor subfamilies that respond to dietary and endogenous ligands and have implications for CVD are emphasized in this article peroxisome proliferator-activated receptors, retinoid X receptors, liver X receptors, and the farnesoid X receptor.