The present application relates to methods and compositions for triggering RNAi. Triggered RNAi is highly versatile because the silencing targets are independent of the detection targets. In some embodiments, a method of silencing a target gene is provided. The method comprises providing an initiator to a cell comprising a detection target and a silencing target gene, wherein the detection target is different from the silencing target gene providing a first substrate monomer to the cell, wherein the first substrate monomer comprises a silencing target complement region that is substantially complementary to a portion of the silencing target gene, and an initiator complement region that is substantially complementary to a portion of the initiator and providing a second substrate monomer to the cell, wherein the second substrate monomer comprises a silencing target region that is substantially complementary to the silencing target complement region wherein binding of the detection target to the initiator initiates formation of an inactivator double-stranded RNA (inactivator dsRNA) which silences the silencing target gene.
