Gene targeting can be loosely defined as a process through which a specific chromosomal sequence is recognized and bound by a reagent designed for the purpose. The endpoint may be modulation of events at the target, such as transcription, or a permanent change in sequence at the site. A facile strategy for mammalian cells would have broad applications in basic and applied research, including gene therapy. Although approaches based on homologous recombination are routinely employed for transgenic animal construction, they are too laborious and inefficient for broader use. Consequently there has been a longstanding interest in developing effective synthetic reagents. Sequence recognition can be either at the level of a single strand or via the major or minor grooves, and specific approaches for each route are under development. In this review several oligonucleotide-based strategies will be discussed. These include single and double strand oligonucleotides designed to attack single strand targets, and triple helix forming olgonucleotides and peptide nucleic acids, intended for double stranded targets.