RNA interference (RNAi) has been greatly exploited in recent years as an increasingly effective tool to study gene function by gene silencing. The introduction of exogenous double-stranded RNA (dsRNA) into a cell can trigger this gene silencing process. An RNase III family enzyme, Dicer, initiates silencing by releasing approximately 20 base duplexes, with 2- nucleotide 3' overhangs called siRNAs. The RNAi pathway also mediates the function of endogenous, noncoding regulatory RNAs called miRNAs. Both miRNAs and siRNAs guide substrate selection by similar if not identical effector complexes called RISCs. These contain single-stranded versions of the small RNA and additional protein components. Of those, the signature element, at the heart of all RISCs, is a member of the Argonaute family of proteins. Our structural and biochemical studies on Argonaute identified this protein as Slicer, the enzyme in RISC that cleaves the mRNA as directed by the siRNA. The role of the Argonautes as Slicers and non-Slicers is discussed.