Ideally, gene therapy involves the correction of genetic defects through the natural means of gene targeting. This therapy possesses a number of conceptual advantages. However, a major obstacle to successful gene therapy is the relative inefficiency of the targeting process in mammalian cells. Gene targeting may be accomplished by two different mechanisms: the homologous recombination and the mismatch correction of DNA heteroduplexes. Based on the model of homologous recombination for the well-studied prokaryotic and the less studied eukaryotic systems, three approaches have been employed to improve the efficiency and accuracy of homologous recombination events. These are: (1) artificial double-strand breaks in both the exogenous and the chromosomal DNA, (2) a contiguous long homology between the exogenous and chromosomal DNA, and (3) a transient overproduction of an active recombinase, the bacterial RecA or mammalian RecA-like proteins, in mammalian cell nuclei. Combining these approaches can result in more effective gene targeting protocols. The second mechanism has been improved based on recent observations of recombinogenic activity of oligonucleotides and, especially, specifically designed chimeric RNA/DNA oligonucleotides. The use of RecA-like proteins to stimulate searching for homology and forming stable DNA heteroduplexes between oligonucleotides and chromosomal DNA remains an attractive idea for additional improvement of gene targeting events.