Over 30 years after the original description of Randle's cycle, the mechanisms by which elevated circulating non-esterified fatty acids might be causally related to glucose intolerance in Type 2 diabetes mellitus remain uncertain. This review examines the evidence that elevated plasma NEFA can inhibit glucose-stimulated insulin secretion by pancreatic beta-cells and impair glucose- and insulin-stimulated glucose disposal by peripheral tissues. Experimental evidence beginning to examine the mechanisms of these phenomena is discussed.