Double-stranded RNA (dsRNA)-induced sequence-specific gene silencing in animals and plants is known as RNA interference. In mammalian cells, although long dsRNAs induce an interferon-mediated, non-specific gene silencing, short interfering RNAs (siRNAs) that are processed from long dsRNAs by Dicer can induce sequence-specific gene silencing. Since siRNAs can be designed for genes of interest, these molecules have great potential to be used as effective gene therapies. In plants, siRNAs targeted to CpG islands within a promoter can also induce RNA-directed DNA methylation. In addition, siRNAs have a role in heterochromatic gene silencing in fission yeasts, plants and animals. Recently, siRNAs were demonstrated to induce transcriptional gene silencing (TGS) via DNA methylation in human cells. This review will focus on TGS by siRNAs, such as DNA methylation and histone methylation.