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To present current perspectives on the mediators and mechanisms of cyto-lipotoxic events and their relevance to human health.The relatively recent isolation of lipid acyltransferase genes from yeast to mice and humans has resulted in a paradigm shift that now establishes all fatty acids as toxic, albeit in tissue specific patterns and by different mechanisms. Furthermore, the dysregulation of glucose homeostasis in combination with excess fatty acids provides a synergistic effect leading to glucolipotoxicity and cell death. These findings are relevant to the development of disease states associated with the pathogenesis of the metabolic syndrome.In an era when an astounding number of people are diagnosed with metabolic disorders, it is imperative that we understand the consequences of a chronic metabolic surplus. Excessive fat, saturated or otherwise, has to be accommodated. Multiple aspects of this homeostasis are emerging, some of which are described here.