Two gene-targeting approaches have been developed with the use of RNase P. The first approach is based on an external guide sequence (EGS), which consists of a sequence complementary to a target mRNA and, when noncovalently complexed with RNase P, renders the target RNA susceptible to degradation by the ribonuclease. The second is involved in the generation of a sequence-specific ribozyme, M1GS, by covalently linking the RNase P catalytic subunit M1 RNA with a guide sequence that is complementary to a target mRNA. Both the M1GS ribozyme and EGS technology have been shown to be efficient and specific in cleaving an target mRNA sequence in vitro, and effective in down-regulating the expression of the target mRNA in cultured cells. This chapter summarizes the recent progress using the RNase P-based technology and offers insights into the future of using EGS and M1GS as tools for basic research and as gene-targeting agents for clinical applications.