Introduction: Sweeteners are substances used to replace sugar. They can either be chemically produced (artificial sweeteners) or extracted from plants (natural sweeteners). In the last two decades, there is an increased popularity in their role as sugar substitutes in individuals to promote weight loss or maintain glycemic control. However, despite their favorable effects, there is concern regarding their side effects and especially their influence in the development of nonalcoholic fatty liver disease (NAFLD).Areas covered: A comprehensive literature search was conducted on Medline including systematic reviews, longitudinal controlled studies, and retrospective cohort studies. We present an up-to-date systematic review of the current literature regarding the safety in artificial and natural sweeteners use as a means of weight loss or diabetes control.Expert opinion: Natural sweeteners have not been associated directly with NAFLD, and on the contrary, some, such as stevia, and trehalose, may have a protective effect. Rare sugars and polyols can be used safely and have significant benefits that include anti-oxidant effect and optimal glycemic control. Artificial sweeteners, due to their effect on NAFLD development and insulin resistance, are not indicated in patients with obesity or diabetes. Further studies in human subjects are required to verify the above findings.