Elevated plasma triglycerides (TGs) are early key features of conditions associated with a dysregulation in glucose metabolism and may predict the development of type 2 diabetes (T2D) over time. Although the acute ingestion of lipid, either mixed with or shortly before the meal, is neutral or slightly beneficial on glucose tolerance, a short-term increase in plasma TGs induced by either an i.v. lipid infusion or a high-fat diet produces a deterioration of glucose control. Accordingly, chronic lowering of plasma TGs by fibrates improves glucose homeostasis and may also prevent T2D. The chronic effects of the elevation of dietary lipid intake are less clear, particularly in humans, being the quality of fat probably more important than total fat intake. Although on the bases of the available experimental and clinical evidence it cannot be easily disentangled, with respect to elevated non-esterified fatty acids (NEFA) the relative contribution of elevated TGs to glucose homeostasis disregulation seems to be greater and also more plausible. In conclusion, although the association between elevated plasma TGs and impaired glucose tolerance is commonly considered not causative or merely a consequence of NEFA-mediated lipotoxicity, the available data suggest that TGs per se may directly contribute to disorders of glucose metabolism.