Antisense oligonucleotides are powerful tools to modify gene expression RNase H that exploit the cellular nuclease activity of RNase H. However, in some cases they have been shown to induce cleavage at sites other than the intended target. On page 58, Ma et al. have investigated the intracellular specificity of an alternative strategy that exploits Rnase P, an enzyme that normally cleaves the 5′ terminus of precursor tRNAs. A synthetic complementary oligonucleotide that mimics structural features of the precursor tRNA, termed the external guide sequence, was used to direct Rnase P to the PKC-α target gene. These EGSs were highly efficient in reducing expression of PKC-α protein and mRNA in cultured cells.