The endoribonuclease RNase P is involved in the processing of tRNA precursors to generate mature 5′ termini. The catalytic activity of RNase P is associated with an RNA, RNase P RNA. A specific interaction between the 3′ end of the substrate and RNase P RNA, to form an RNase P RNA-substrate complex, is referred to as the ‘73–294-interaction’. This interaction has an important role for efficient and correct cleavage to occur. Here our understanding of the contribution of the 73–294-interaction and metal ions, with respect to efficient and correct cleavage in RNase P RNA-mediated catalysis, will be discussed.