Endogenously produced small interfering RNAs (endo-siRNAs, 18–30 nucleotides) play a key role in gene regulatory pathways, guiding Argonaute effector proteins as a part of a functional ribonucleoprotein complex called the RISC (RNA induced silencing complex) to complementarily target nucleic acid. Enabled by the advent of high throughput sequencing, there has been an explosion in the identification of endo-siRNAs in all three kingdoms of life since the discovery of the first microRNA in 1993. Concurrently, our knowledge of the variety of cellular processes in which small RNA pathways related to RNA interference (RNAi) play key regulatory roles has also expanded dramatically. Building on the strong foundation of RNAi established over the past fifteen years, this review uses a historical context to highlight exciting recent developments in endo-siRNA pathways. Specifically, my focus will be on recent insights regarding the Argonaute effectors, their endo-siRNA guides and the functional outputs of these pathways in several model systems that have been longstanding champions of small RNA research. I will also touch on newly discovered roles for bacterial Argonautes, which have been integral in deciphering Argonaute structure and demonstrate key functions of these conserved pathways in genome defense.
