Human intestinal enzymes do not hydrolyze non-digestible carbohydrates (NDCs), and thus, they are not digested and absorbed in the small intestine. Instead, NDCs are partially to completely fermented by the intestinal microbiota. Select NDCs are associated with health benefits such as laxation, and blood cholesterol and glucose-lowering effects. NDCs provide functional attributes to processed foods, including sugar or fat replacers, thickening agents, and bulking agents. Additionally, NDCs are incorporated in processed foods to increase their fiber content. Although consumption of NDCs can benefit health and contribute functional characteristics to foods, they can cause gastrointestinal symptoms, such as flatulence and bloating. As gastrointestinal symptoms negatively affect consumer well-being and their acceptance of foods containing NDC ingredients, it is crucial to consider tolerance when designing food products and testing their physiological health benefits in clinical trials. This perspective provides recommendations for the approach to assess gastrointestinal tolerance to NDCs, with a focus on study design, population criteria, intervention, comparator, and outcomes. Special issues related to studies in children and implications for stakeholders also are discussed. It is recommended that the evaluation of gastrointestinal tolerance to NDCs be conducted in randomized, blinded, controlled crossover studies using standard gastrointestinal questionnaires, with attention to study participant's background diets, health status, lifestyle, and medications.