The potential contribution of lipids to insulin signaling has excited interest because of the notion that cholesterol and sphingolipids form functional microdomains-lipid rafts-in cell membranes and that these domains may affect signal transduction. In this Perspective, we discuss the evidence suggesting that cholesterol-sphingolipid rafts play a role in the pathogenesis of insulin resistance. The data relating insulin signaling to lipid rafts in the main insulin target tissues are briefly summarized, including partially controversial findings on the role of caveolae versus other types of rafts. In addition, recent results pointing toward the importance of raft perturbations in the pathogenesis of insulin resistance are discussed. Notably, several studies suggest a correlation between membrane lipid composition and insulin sensitivity. We put forward the idea that the dyslipidemic changes typically associated with insulin resistance and metabolic syndrome may impair the functionality of rafts in insulin target cells, thereby promoting insulin resistance.