This review provides an overview of the interrelationships among the diet, gut microbiota, and health status and then focuses specifically on published research assessing the relationship of low-/no-calorie sweeteners (LNCSs) to selected aspects of the gut microbiota. Microbiome research is expanding as new data on its role in health and disease vulnerability emerge. The gut microbiome affects health, digestion, and susceptibility to disease. In the last 10 years, investigations of LNCS effects on the gut microbiota have proliferated, although results are conflicting and are often confounded by differences in study design such as study diet, the form of the test article, dosage, and study population. Staying current on microbiome research and the role of dietary inputs, such as LNCSs, will allow healthcare and nutrition practitioners to provide evidence-based guidance to the individuals they serve.