This study describes a mechanism by which small RNAs expressed in neurons may contribute to long-term memory. The authors discovered an abundance of PIWI-interacting RNAs (piRNAs) in Aplysia neurons that seem to control the epigenetic regulation of the transcription factor cyclic AMP-responsive element-binding protein 2 (CREB2) — a repressor of long-term memory function. In response to serotonin, piRNAs facilitates methylation of the CREB2 promoter, thereby silencing gene expression. This results in enhanced long-term synaptic changes in the functional state of neurons, suggesting that piRNAs regulate memory storage through an epigenetic mechanism and showing a role for piRNAs outside of the germ line.