Several ways that RNAi can regulate viruses in mammalian cells. Left: cell-endogenous endo-miRNAs are engaged in RISC complexes to target partially homologous viral transcripts. Middle: virus-encoded miRNA can be processed as exo-miRNAs that are engaged with RISC for interaction with other viral RNAs. Right: viruses that contain shRNA sequences (for example, lentiviral shRNA libraries) are processed into exo-siRNAs. The double-stranded RNAs (hairpins) are processed in the RISC into single-stranded guide RNAs that bind to complementary sequences in the mRNA, thus recruiting RISC, which degrades the mRNA or inhibits its translation. Transposable elements and endogenous retroviruses produce endo-siRNAs in mammalian cells. Both exo-siRNAs and endo-siRNAs can be incorporated into RISC complexes in mammalian cells to silence homologous target RNAs. Multiple transcripts (blue) are indicative of differently spliced RNAs.