A key metabolic activity of the gut microbiota is the fermentation of dietary fibre, which generates short-chain fatty acids (SCFAs) as the principal end products. SCFAs are absorbed from the gut lumen and can contribute to energy homeostasis by serving as an available substrate at different organ sites, including skeletal muscle. Furthermore, a widespread receptor system exists for SCFAs. These G protein-coupled receptors, free fatty acid receptor 2 (FFAR2) and 3 (FFAR3) are expressed in numerous tissues and regulate metabolic responses in the gut epithelium, adipose tissue and liver. This talk will evaluate the evidence demonstrating that SCFAs mediate metabolic cross-talk between the gut microbiota and skeletal muscle. It will discuss the direct and indirect mechanisms through which raising gut-derived SCFAs modules skeletal muscle metabolism. Finally, it will highlight the potential roles of these gut-derived metabolites in exercise performance and adaptations to exercise training.