Dietary fat intake is an environmental factor that affects many aspects of human health. 1 Several lines of evidence suggest that common diseases of modern society are associated with high-fat Western diets combined with a sedentary lifestyle. 2 For example, diabetes, obesity, and cardiovascular disease are major causes of mortality and morbidity whose incidence tracks with the rate of industrialization in many countries. 3 Conversely, it has been established that caloric restriction with low-fat diets in rodents and primates leads to increased longevity and lower incidence of metabolic and cardiovascular disorders. 4 Interestingly not all dietary fat is bad; diets high in monounsaturated fatty acids (the Mediterranean diet) or polyunsaturated fatty acids (the Eskimo diet) appear to have cardioprotective effects. 5, 6 The epidemiology of human metabolic diseases and animal feeding studies support the proposal that caloric intake plays an important role in the regulation of lipid metabolism, insulin sensitivity, glucose homeostasis, and atherosclerosis. 1, 7 It is therefore not surprising that mammals have evolved with hormonal systems to regulate the physiological response to dietary intake of fatty acids. 8 A family of transcription factors known as the Peroxi-some Proliferator-Activated Receptors (PPARs) plays a central role in regulating the storage and catabolism of dietary fats. The PPARs were cloned less than a decade ago as orphan members of the nuclear receptor gene family that includes the receptors for the steroid, retinoid, and thyroid hormones. 9, 10 This review covers the rapid progress in the functional analysis of these orphan receptors, research which has led to a greater understanding of the importance of fatty acids as hormones and has established the PPARs as molecular targets for the development of drugs to treat human metabolic diseases.