An extensive literature base combined with advances in sequencing technologies demonstrate microRNA levels correlate with various metabolic diseases. Mechanistic studies also establish microRNAs regulate central metabolic pathways and thus play vital roles in maintaining organismal energy balance and metabolic homeostasis. This review highlights research progress on the roles and regulation of microRNAs in the peripheral tissues that confer insulin sensitivity. We discuss sequencing technologies used to comprehensively define the target spectrum of microRNAs in metabolic disease that complement studies reporting physiologic roles for microRNAs in the regulation of glucose and lipid metabolism in animal models. We also discuss the emerging roles of exosomal microRNAs as endocrine signals to regulate lipid and carbohydrate metabolism.