Piwi-associated small RNAs (piRNAs) function in the germline to silence transposons by transcriptional and post-transcriptional mechanisms. Now, Eric Kandel, Thomas Tuschl and colleagues show that piRNAs are expressed in the central nervous system in the sea slug, Aplysia, where they regulate transcription of the plasticity-related gene CREB2 (Cell 149, 693–707, 2012). The authors initially identified neuronal piRNAs in a small RNA library, and they also identified piRNA-Piwi protein complexes in neural cells. They used cultured neurons to show that piRNAs are regulated by the neuromodulator serotonin and that Piwi functions to enhance serotonin-dependent long-term synaptic facilitation, as measured electrophysiologically in co-cultured sensory and motor neurons. They found that Piwi and the piRNA piR-F specifically repress CREB2, and they show that CREB2 is regulated by serotonin-dependent promoter methylation. This work suggests a broader role for piRNA-mediated regulation of expression in somatic tissues beyond their role in the germline and provides insight into epigenetic mechanisms of memory formation.