<p>There is much interest in the role of sweeteners such as table sugar (sucrose) and high-fructose corn syrup in obesity and metabolic disease. Both sweeteners consist of glucose and fructose, two six-carbon isomeric sugars. Whereas glucose ingestion may promote obesity through its effects to stimulate insulin secretion, fructose has unique metabolic effects that promote triglyceride synthesis and fat accumulation. These effects arise from fructose’s well-known role as a signal of metabolic plenty. Under modern conditions of overnutrition, chronic excess fructose drives features of metabolic syndrome. Emerging evidence further links fructose to cancer and dementia. Here we review the biochemical, molecular and physiological distinctions between fructose and glucose, as well as the endogenous fructose pathway that makes fructose from glucose. Through this Review, we highlight the role of fructose not only as a caloric source, but also as a regulator of metabolic health and disease.</p>