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Over the past five years, the importance of a diverse class of 18–24 nucleotide RNA molecules, known as microRNAs (miRNAs) has increasingly been recognized. These highly conserved RNAs regulate the stability and translational efficiency of complementary target messenger RNAs. The human genome is now predicted to encode nearly 1,000 miRNAs that likely regulate at least one third of all human transcripts. Despite rapid progress in miRNA discovery, the physiologic functions of only a small number have been definitively established. In this review, we discuss the principles of miRNA function that have emerged from the studies performed thus far in vertebrates. We also discuss known and potential roles for miRNAs in human disease states and discuss the influence of human genetic variation on miRNA-mediated regulation.