RNAs are versatile regulators of gene expression.RNA secondary structures are known to be important for regulatory functions by various types of RNA molecules.MicroRNAs are small non-coding RNAs that repress protein synthesis by binding to target mRNAs in multicellular eukaryotes.Target identification of microRNA targets is essential to fully understand this new dimension of the complex gene regulatory networks.By employing our Sfold RNA folding program (http://sfold.wadsworth.org)and a two-step model for modeling microRNA:target hybridization, we found that secondary structure of target has a major impact on target recognition of microRNAs.Based on the analysis of large microRNA targeting data with the model parameters and other sequence and conservation features, we have recently developed a novel computational framework that offers major improvement over established algorithms for prediction of microRNA targets.Computational tools are available through Sfold web server.