Several studies, some of which have been updated during the recent workshop entitled Genome Medicine: Gene Therapy for the Millennium (Rome, 30 September–3 October 2001), have highlighted the usefulness of extrachromosomal or episomal genes in gene targeting strategies. Due to the selectable nature of antibiotic resistance and reporter genes, targeted correction of mutated versions of these extrachromosomal genes allows an accurate quantification of correction frequency. In addition, these model systems facilitate and speed up the optimization of critical parameters for the successful application of gene targeting approaches. In fact, type of cell line, gene delivery system, molar ratio of episomal target/therapeutic constructs, nature and design of therapeutic complexes and different recombinative proteins may be critical for the actual feasibility of each method. Although virus-based approaches are now being investigated as well, this article is focusing on the targeted correction of extrachromosomal genes by the use of small DNA fragments (SDF), chimeric RNA/DNA oligonucleotides (RDO) and triplex-forming oligonucleotides (TFO).