Diets rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs), such as alpha-linoleic acid, eicosapentaenoic acid, and docosahexaenoic acid, are associated with decreased incidence and severity of coronary heart disease. Similarly, conjugated linoleic acids (CLAs), which are found in meat and dairy products, have beneficial effects against atherosclerosis, diabetes, and obesity. The effects of n3-PUFAs and CLAs are in contrast to fatty acids with virtually identical structures, such as linoleic acid and arachidonic acid (ie, n-6 PUFAs). This article discusses the possibility that cognate receptors exist for fatty acids or their metabolites that are able to regulate gene expression and coordinately affect metabolic or signaling pathways associated with coronary heart disease. Three nuclear receptors are emphasized as fatty acid receptors that respond to dietary and endogenous ligands peroxisome proliferator activated receptors, retinoid X receptors, and liver X receptors.