The metabolic syndrome is discussed in terms of insulin resistance linked to an increased regulation of metabolism by cortisol and fatty acids. This change in hormonal balance is associated with diabetes, android (visceral) obesity, hypertension, hypertriglyceridemia, hyperapobetalipoproteinemia and low concentrations of HDL; a cluster of risk-factors that predisposes to the development of premature atherosclerosis. It is proposed that the metabolic syndrome is accompanied by a derangement in the hypothalamic-pituitary-adrenal-axis such that the effects of cortisol are exaggerated relative to those of CRF. Excessive action of fatty acids and cortisol causes insulin resistance and increase the hepatic secretion of glucose and VLDL. Furthermore, cortisol can decrease the uptake of LDL by the liver. Cortisol in the presence of relatively high insulin concentrations can promote the deposition of energy and lead to obesity. Chronic treatment of rats with D-fenfluramine has been shown to decrease the release of cortisol and fatty acids in response to stress, and to improve insulin sensitivity. The effects of D-fenfluramine were also tested in male JCR:LA corpulent rats which are prone to develop atherosclerosis and myocardial lesions. D-fenfluramine improved insulin sensitivity, decreased the hypertriglyceridemia, and prevented the development of necrotic myocardial lesions caused by ischemia. The data presented demonstrates a link between excessive action of cortisol and fatty acids in predisposing to insulin resistance and the pathologies that are associated with the metabolic syndrome.