MicroRNAs are small, non-coding RNAs that posttranscriptionally regulate gene expression mainly by binding to the 3'UTR of their target mRNAs. Recent data revealed that microRNAs have ail important role in pancreas and liver development and physiology. Using cloning and microarray profiling approaches, we show chat a unique repertoire of microRNAs is expressed at the onset of liver and pancreas organogenesis. and in pancieas and liver at key stages of cell face determination Among the microRNAs that are expressed at these stages, miR-495 and miR-218 were predicted to, respectively, target the Onecut (OC) transcription factors Hepatocyte Nuclear Factor-6 (HNF-6/OC-1) and OC-2. two important regulators of liver and pancreas development MiR-495 and miR-218 are dynamically expressed in developing liver and pancreas, and by transient transfection. we show that they target HNF-6 and OC-2 3'UTRs Moreover, when overexpressed in cultured cells, miR-495 and miR-218 decrease the endogenous levels of HNF-6 and OC-2 mRNA. These results indicate that the expression of regulators of liver and pancreas development is modulated by microRNAs They also suggest a developmental role for miR-495 and miR-218 (C) 2009 Elsevier Inc All rights reserved