Recent epidemiological evidence points to a link between a variety of negative health outcomes (e.g. metabolic syndrome, diabetes and cardiovascular disease) and the consumption of both calorically sweetened beverages and beverages sweetened with high-intensity, non-caloric sweeteners. Research on the possibility that non-nutritive sweeteners promote food intake, body weight gain, and metabolic disorders has been hindered by the lack of a physiologically-relevant model that describes the mechanistic basis for these outcomes. We have suggested that based on Pavlovian conditioning principles, consumption of non-nutritive sweeteners could result in sweet tastes no longer serving as consistent predictors of nutritive postingestive consequences. This dissociation between the sweet taste cues and the caloric consequences could lead to a decrease in the ability of sweet tastes to evoke physiological responses that serve to regulate energy balance. Using a rodent model, we have found that intake of foods or fluids containing non-nutritive sweeteners was accompanied by increased food intake, body weight gain, accumulation of body fat, and weaker caloric compensation, compared to consumption of foods and fluids containing glucose. Our research also provided evidence consistent with the hypothesis that these effects of consuming saccharin may be associated with a decrement in the ability of sweet taste to evoke thermic responses, and perhaps other physiological, cephalic phase, reflexes that are thought to help maintain energy balance.