Silencing of multicopy transgenes is thought to occur via production of double-stranded RNAs, which are processed by Dicer to small interfering RNAs (siRNAs) that are loaded onto Argonaute proteins to target transcriptional or post-transcriptional silencing. Now, Craig Mello and colleagues and Shawn Ahmed, Eric Miska and colleagues separately report that piwi-interacting RNAs (piRNAs) can initiate stable, heritable epigenetic silencing in the germline of Caenorhabditis elegans (Cell 150, 65–77, 2012, and Cell 150, 88–99, 2012). Both groups use single-copy insertion transgenes to identify a pathway involving chromatin-associated factors and RNA interference (RNAi) components that are required for the maintenance of multigenerational silencing. Both groups find that piRNAs are required for initiation but not maintenance of silencing. This work suggests a new mechanism of transgene silencing that is independent of the production of siRNAs from double-stranded RNA. The authors suggest that piRNAs may scan the genome for foreign sequences and initiate targeted silencing.