Inhibition of translation by duplex RNA (siRNA) complementary to mRNA is a powerful approach to silencing genes in mammalian cells and RNA interference (RNAi) is an important natural biological mechanism for controlling gene expression. Anti-mRNA duplexes are widely used for laboratory studies, target validation, and therapeutic development. Endogenously expressed duplex RNAs (microRNAs, miRNAs) have been shown to target mRNA and be natural regulators of expression. Recently, we have shown that peptide nucleic acids (PNAs) or duplex antigene RNAs (agRNAs) that target DNA sequences can also inhibit gene transcription. These findings extend gene silencing to targets within chromosomal DNA.