Molecules that can specifically silence gene expression are powerful research tools. Much effort has been put into the development of such molecules and has resulted in the creation of different classes of potential therapeutic agents. Small interfering RNA (siRNA) is one of the latest additions to the repertoire of sequence-specific gene-silencing agents. The robustness of this approach has motivated numerous biotechnology organizations and academic institutions to develop siRNA libraries for high-throughput genome-wide screening in mammalian cells. This article first overviews current nucleic-acid-based approaches for gene silencing, and then focuses on the application of siRNAs in particular in functional genomics and as potential therapeutics.