Consumption of excessive amounts of added sugars and their effects on human health has been a major concern in the last several decades. Epidemiological data suggest that the incidence of metabolic disorders, such as obesity, nonalcoholic fatty liver disease, cardiovascular disease and diabetes, has increased due to chronic surplus consumption of these sugars. While many of these sugars have been isolated and studied for centuries, their health impacts and exact underlying mechanisms are still unclear. In this review, we discuss the pathophysiological role of 6 major simple sugars present in the human diet and the biochemical and molecular pathways related to their metabolism by different organs and gut microbiota, with a focus on the most recent investigations.