Hepatitis delta virus (HDV) contains two self-cleaving RNA sequences (ribozymes) that may naturally function as such in human cells. A pseudo-knot-containing structural motif, which is distinct from the well-characterized secondary structures of self-cleaving RNAs common to the plant pathogenic RNAs, is shared by the cis-acting HDV ribozymes. Definition of the sequences and secondary structures of the HDV ribozymes has facilitated the design of novel catalytic molecules, such as small RNA circles, capable of site-specific cleavage of RNA in trans.