The study investigates the effectiveness of microRNA (miRNA) target sites in mammalian mRNAs, focusing on both canonical and non-canonical interactions. The authors found that recently reported non-canonical sites do not mediate repression despite binding to miRNAs, suggesting that the majority of functional sites are canonical. They developed an improved quantitative model of canonical targeting using a compendium of experimental datasets, which considered site type and 14 other features to predict the most effectively targeted mRNAs. This model outperformed existing models and was as informative as high-throughput in vivo crosslinking approaches. The model is integrated into the latest version of TargetScan (v7.0), providing a valuable resource for placing miRNAs into gene-regulatory networks.The study investigates the effectiveness of microRNA (miRNA) target sites in mammalian mRNAs, focusing on both canonical and non-canonical interactions. The authors found that recently reported non-canonical sites do not mediate repression despite binding to miRNAs, suggesting that the majority of functional sites are canonical. They developed an improved quantitative model of canonical targeting using a compendium of experimental datasets, which considered site type and 14 other features to predict the most effectively targeted mRNAs. This model outperformed existing models and was as informative as high-throughput in vivo crosslinking approaches. The model is integrated into the latest version of TargetScan (v7.0), providing a valuable resource for placing miRNAs into gene-regulatory networks.