Secondary Endogenous Small and Interfering In many eukaryotes, Piwi proteins bind small noncoding Piwi-interacting RNAs (piRNAs) that function to silence transposons in the germ line and protect the germ line from transposable element–driven recombination and mutation. Bagijn et al. (p. 574 , published online 14 June; see the Perspective by Xiol and Pillai ) show that in the nematode, Caenorhabditis elegans , a messenger RNA (mRNA) that contains a piRNA target sequence gives rise to a second, downstream class of small RNAs known as secondary endogenous small interfering RNAs, or endo siRNAs. These endo siRNAs map to the vicinity of the piRNA complementary sequence in the mRNA target and depend on both Piwi and on factors involved in the related RNA interference pathway for their genesis, but not on the Piwi slicer activity. Mapping the endo siRNAs reveals that piRNAs can target imperfectly matched targets and that piRNAs target a subset of both transposons and endogenous genes for silencing.