Background: Sugars have emerged as one of the most important public health concerns. Attention has focused particularly on fructose-containing sugars (fructose, sucrose, high fructose corn syrup, honey, etc), which collectively have been indicted as drivers of various cardiometabolic complications. This special view rests on the unique metabolic and endocrine responses to fructose. Unlike glucose, fructose is thought to bypasses negative feedback controls acting as an unregulated substrate for de novo lipogenesis and impair satiety signaling resulting in weight gain. In support of these mechanisms, animal models, low-quality ecological studies, and select human trials of overfeeding at levels of exposure far beyond population intakes have reported adverse metabolic effects of sugars. Higher level evidence from systematic reviews and meta-analyses of controlled trials, however, suggests that any effects of sugars are mediated by excess calories rather than the sugars per se. It remains unclear whether fructose-containing sugars contribute to cardiometabolic complications independent of their calories.