The important role that noncoding RNA plays in cell biology makes it an attractive target for molecular recognition. However, the discovery of small molecules that bind double helical RNA selectively and may serve as biochemical probes and potential drug leads has been relatively slow. Herein, we show that peptide nucleic acids, as short as six nucleobases, bind very strongly (K(a) > 10(7)) and sequence selectively to a homopurine tract of double helical RNA at pH 5.5. The isothermal titration calorimetry and circular dichroism experiments suggest that the binding mode may be a sequence selective triple helix formation. Our results have implications for development of biochemical probes to study function of noncoding RNAs and design of compounds with potential antibacterial and antiviral activity.