Triple helix-forming oligonucleotides (TFOs) can bind to polypurine/polypyrimidine regions in DNA in a sequence-specific manner. The resulting triplexes have been shown to constitute a DNA structure that can provoke binding by the damage recognition factors, XPA and RPA, and to stimulate DNA repair via the nucleotide excision repair (NER) pathway. Based on these observations, experiments were undertaken to determine the extent to which triplex structures can stimulate recombination events within genomic DNA in a site-directed manner. Studies in which TFOs were targeted to episomal SV40 genomes in COS cells suggested that intermolecular triplexes could stimulate recombination between tandemly repeated reporter gene sequences in a pathway dependent on XPA and other NER factors. Experiments in mouse Ltk-cells containing a dual TK gene substrate demonstrated that intrachromosomal gene conversion could be provoked by high affinity triplex formation, at frequencies as high as 1-2%, if the TFOs were delivered into the cells by microinjection. Recent work in both COS cells using an episomal target and in human cell free extracts using plasmid substrates has further demonstrated that triplex formation can promote intermolecular recombination. TFOs were shown to induce recombination between a target gene and short DNA fragment, in cases where the fragment is either covalently linked to or is completely separate from the TFO. In the extracts, immunodepletion and complementation with purified proteins demonstrated a requirement for XPA and for the human recombinase, HsRad51, in the reaction. In recent work, the ability of TFOs to stimulate recombination and thereby mediate gene repair in a dose-dependent manner at a chromosomal locus in mammalian cells has been established. Overall, this work raises the possibility that DNA binding ligands such as TFOs and related molecules such as a peptide nucleic acids (PNAs) may be useful in strategies designed to mediate targeted genome modification and genetic therapy by stimulating recombination in site-specific manner.