G-protein-coupled receptors are a diverse class of cell surface receptors that orchestrate numerous physiological functions. The G-protein-coupled receptors, GPR41 and GPR43, sense short-chain fatty acids (SCFAs), which are metabolites of dietary fermentation by the host’s intestinal bacteria. These receptors have gained attention as potential therapeutic targets against various diseases because of their SCFA-mediated beneficial effects on the host’s intestinal health. Mounting evidence has associated the activity of these receptors with chronic metabolic diseases, including obesity, diabetes, inflammation, and cardiovascular disease. However, despite intensive research using various strategies, including gene knockout (KO) mouse models, evidence about the precise roles of GPR41 and GPR43 in disease treatment remains inconsistent. Here, we comprehensively review the latest findings from functional studies of the signaling mechanisms that underlie the activities of GPR41 and GPR43, as well as highlight their multifaceted roles in health and disease. We anticipate that this knowledge will guide future research priorities and the development of effective therapeutic interventions.