miRNAs associate with Argonaute (AGO) proteins to silence the expression ofmRNAtargets by inhibiting translation and promoting deadenylation, decapping, andmRNAdegradation. A current model for silencing suggests thatAGOs mediate these effects through the sequential recruitment ofGW182 proteins, theCCR4-NOTdeadenylase complex and the translational repressor and decapping activatorDDX6. An alternative model posits thatAGOs repress translation by interfering witheIF4A function during 43S ribosomal scanning and that this mechanism is independent ofGW182 and theCCR4-NOTcomplex inDrosophila melanogaster Here, we show that miRNAs,AGOs,GW182, theCCR4-NOTcomplex, andDDX6/Me31B repress and degrade polyadenylatedmRNAtargets that are translated via scanning-independent mechanisms in both human andDmcells. This and additional observations indicate a common mechanism used by these proteins and miRNAs to mediate silencing. This mechanism does not requireeIF4A function during ribosomal scanning.