Maintenance of homeostasis during environmental flux requires constant metabolic adjustment, achieved partly through the fine regulation of gene expression. MicroRNAs are key players in this regulatory milieu; they have been implicated in regulating gene expression within several metabolically active tissues including the endocrine pancreas, liver and adipose tissue. Recent studies, for example, implicate miR-375 in pancreatic islet cell viability and function, and removal or overexpression of miR-375 profoundly affects glucose metabolism. In the liver, miR-122 is important for normal lipid metabolism. In fact, misexpression of miRNAs can occur in some diseases, suggesting that restoring miRNA expression is a potential therapeutic approach for both metabolic syndrome and diabetes.