Carbohydrate ingestion can improve endurance exercise performance. In the past two decades, research has repeatedly reported the performance benefits of formulations comprising both glucose and fructose (GLUFRU) over those based on glucose (GLU). This has been usually related to additive effects of these two monosaccharides on the gastrointestinal tract whereby intestinal carbohydrate absorption is enhanced and discomfort limited. This is only a partial explanation, since glucose and fructose are also metabolized through different pathways after being absorbed from the gut. In contrast to glucose that is readily used by every body cell type, fructose is specifically targeted to the liver where it is mainly converted into glucose and lactate. The ingestion of GLUFRU may thereby profoundly alter hepatic function ultimately raising both glucose and lactate fluxes. During exercise, this particular profile of circulating carbohydrate may induce a spectrum of effects on muscle metabolism possibly resulting in an improved performance. Compared to GLU alone, GLUFRU ingestion could also induce several non-metabolic effects which are so far largely unexplored. Through its metabolite lactate, fructose may act on central fatigue and/or alter metabolic regulation. Future research could further define the effects of GLUFRU over other exercise modalities and different athletic populations, using several of the hypotheses discussed in this review.