The prevalence of obesity and type 2 diabetes mellitus has increased concomitantly with the introduction of nutrients with high caloric density and more sedentary lifestyle in western societies. The tight association between insulin resistance and weight gain is likely to play a pivotal role in this “epidemic.” During the last decade, the relationship between nutrient availability and insulin action has been object of intense debate and novel hypotheses have emerged (1–10). A common theme is that the availability of nutrients per se may modulate insulin action toward nutrient storage and disposal within the framework of a homeostatic system designed to regulate energy balance at the cellular and whole body level. Consistent with this view, insulin resistance is acquired as an “adaptation” to nutrient excess. This hypothesis rests on the existence of biochemical pathways capable of ‘sensing’the availability of nutrients and activating the appropriate metabolic/endocrine responses. The current brief perspective is centered on the pleiotropic functions of one of these nutrient sensing pathways, the hexosamine biosynthesis pathway.