The excessive dietary consumption of sugars is currently one of the key factors that have been associated with the development of the global obesity pandemic. To avoid high sugar intake, alternative sweeteners are of increasing interest and play an important role in food and beverage industry. Among sweeteners, natural sugar substitutes, which possess low/no calorie or intense sweetness, and various biological activities, provide ideal alternatives to caloric sugars such as sucrose and high fructose corn syrup. Therefore, this review focuses on several representative natural sweeteners: low-calorie carbohydrates (e.g., erythritol, l -arabinose, d -allulose, and d -tagatose) and high-potency sweet-tasting compounds (e.g., steviol glycosides, mogrosides, glycyrrhizin, and thaumatin). A comprehensive review of sugar substitutes is presented, including their characteristics and practical applications as well as a discussion on their effect on the obesity issue and emerging technologies that offer an alternative biosynthesis pathway to the traditional extraction method.