RNA-induced silencing complexes (RISCs) are multiple-turnover entities that direct many rounds of site-specific target mRNA cleavage (1 ). A principal RISC component in all eukaryotes is a member of the Argonaute (AGO) protein family (4 ). AGO contains the conserved PAZ and PIWI domains, and seems to be the sole protein required for RISC-mediated activities (5). The discovery that the PIWI domain adopts a ribonuclease (RNase) H fold (6 –8 ) has led to a concept of AGO as an “mRNA slicer” component of the miRNA-programmed or small interfering RNA (siRNA)-programmed RISC. The cleavage of the mRNA target occurs between the nucleotides that are complementary to positions 10 and 11 of the miRNA that guides the RISC to cleave its target mRNA, and is defined by the 5′ end of the guide RNA strand (9 ,10 ). This distance-dependent mechanism is now beginning to be understood in precise terms of structural constraints imposed on the target mRNA recognition by the molecular architecture of the AGO/guide RNA complex (11 ,12 ).