The application of low-calorie sweeteners (LCS) in foods and beverages has increased over the past 35 y. At the same time, many characteristics of the American diet have changed, including variations in fat and carbohydrate content and composition, increased nutrient additions, and new dietary patterns due to changing lifestyles and attitudes toward food and the changing cost of food. During this same time period, the prevalence of overweight and obesity has increased from ~30 to 70% of adults in the United States. Clearly, these trends lead to a variety of hypotheses and efforts to explain the role of LCS in this association. The aim of this review is to gain clarity on the role of LCS in weight management and their impact on diet quality. In addition, because the majority of studies aimed at identifying associations between LCS and these outcomes are based on observational data, the pitfalls in designing and evaluating data from observational studies are also discussed. We conclude that there is no evidence that LCS can be claimed to be a cause of higher body weights in adults. Similarly, evidence supporting a role for LCS in weight management is lacking. Due to the confounders in most observational studies, randomized controlled trials are needed to advance understanding.