Fructose consumption per capita has increased markedly over the past decades and is thought to be related with the increased incidence of obesity and metabolic disorders worldwide. Fructose metabolism is mainly hepatic, for its first step at least, and does not require insulin. It was therefore initially thought to be of potential benefit in the dietary management of patients with impaired glucose homeostasis. Long term fructose administration, however, led to the development of hypertriglyceridemia in humans. In addition, it was associated with the development of impaired glucose homeostasis and high blood pressure in rodents. Stimulation of de novo lipogenesis is a major effect of dietary fructose. Recent evidence indicates that hepatic de novo lipogenesis may be directly linked to intrahepatic fat accumulation and hepatic insulin resistance. Furthermore, hyperlipidemia secondary to enhanced hepatic de novo lipogenesis may possibly lead to lipid accumulation in muscle and muscle lipotoxicity, thus resulting in impaired muscle glucose metabolism. This article reviews the present state of knowledge regarding the effects of fructose on whole body lipid metabolism and its possible relationship with the metabolic syndrome.