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MicroRNAs have been described as important regulators of skeletal muscle differentiation and development, but the role of microRNAs in glucose and lipid metabolism is less well established. Here we review the microRNAs involved in insulin resistance and glucose metabolism, as well as microRNAs regulating lipid metabolism and mitochondrial functions in skeletal muscle, with an emphasis on metabolic disorders such as type 2 diabetes and the adaptive response to exercise training. Finally, we raise some methodological considerations for studying microRNAs, as well as challenges investigators may face when elucidating the direct role of microRNAs in the regulation of glucose and lipid metabolism in skeletal muscle. This article is part of a Special Issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernandez-Hernando and Yajaira Suarez.