Low calorie sweeteners (LCS) are prevalent in the food supply for their primary functional property of providing sweetness with little or no energy. Though tested for safety individually, there has been extremely limited work on the efficacy of each LCS. It is commonly assumed all LCS act similarly in their behavioral and physiological effects. However, each LCS has its own chemical structure that influences its metabolism, making each LCS unique in its potential effects on body weight, energy intake, and appetite. LCS may have different behavioral and physiological effects mediated at the sweet taste receptor, in brain activation, with gut hormones, at the microbiota and on appetitive responses. Further elucidation of the unique effects of the different commercially available LCS may hold important implications for recommendations about their use for different health outcomes.