Suspicion that fructose-containing caloric sweeteners (FCCS) may play a causal role in the development of metabolic diseases has elicited intense basic and clinical research over the past 10 years. Prospective cohort studies converge to indicate that FCCS, and more specifically sugar-sweetened beverages (SSBs), consumption is associated with weight gain over time. Intervention studies in which FCCS or SSB consumption is altered while food intake is otherwise left ad libitum indicate that increased FCCS generally increases total energy intake and body weight, while FCCS reduction decreases body weight gain. Clinical trials assessing the effects of SSB reduction as a sole intervention however fail to observe clinically significant weight loss. Many mechanistic studies indicate that excess FCCS can cause potential adverse metabolic effects. Whether this is associated with a long-term risk remains unknown. Scientific evidence that excess FCCS intake causes more deleterious effects to health than excess of other macronutrients is presently lacking. However, the large consumption of FCCS in the population makes it one out of several targets for the treatment and prevention of metabolic diseases.