microRNAs (miRNAs) regulate gene expression, but whether this involves inhibition of translation or altered mRNA decay is debated. Here, the authors observed that mRNA destabilization only occurred for mRNAs that had been translationally repressed (through removal of translation initiation factors), suggesting that translation inhibition preceeds mRNA degradation. Analysis of the role of different translation initiation factors revealed that the RNA helicase eIF4A2 is the only initiation factor necessary, and its knockdown decreased miRNA-mediated repression. Further examination indicated that eIF4A2 interacts with CCR4–NOT1, a complex that promotes deadenylation of miRNA-destabilized transcripts. The authors propose that miRNA-mediated mRNA repression first requires translation inhibition, directed by eIF42A, and then mRNA destabilization and degradation.