Fragile-X syndrome is caused by CGG trinucleotide repeat expansion and silencing of the X-linked FMR1 gene. Now, Samie Jaffrey and colleagues show that an RNA-directed gene silencing mechanism drives epigenetic silencing of FMR1 (Science 343, 1002, 2014). The expanded CGG repeat is transcribed as part of the FMR1 5′ UTR and forms a hairpin structure. The authors investigated the role of this transcript in FMR1 silencing. They used human embryonic stem cells that carry an FMR1 allele with expanded CGG repeats; these cells undergo FMR1 silencing upon neuronal differentiation. The authors first showed that knockdown of FMR1 mRNA inhibited FMR1 silencing, and they then showed that altering the hairpin structure of the CGG repeats with a small molecule that selectively binds the hairpin also prevented FMR1 silencing. In addition, the authors showed that expanded FMR1 transcripts bind to the FMR1 promoter and form an RNA-DNA duplex, and treatment with the small molecule that alters the hairpin structure of the FMR1 transcript reduced binding to the promoter. This work provides a mechanism linking trinucleotide repeat expansion with promoter silencing.