Epigenetics is the study of meiotically and mitotically heritable changes in gene expression which are not coded for in the DNA. Three distinct mechanisms appear to be intricately related and implicated in initiating and/or sustaining epigenetic modifications; DNA methylation, RNA-associated silencing, and histone modifications. It has recently become clear in human cells that RNA plays a far more profound and complex role in regulating the expression of the gene. This regulatory effect is through RNA-associated silencing, can be transcriptional in nature, and is operable through an RNA interference based mechanism (RNAi) that is specifically mediated by small-interfering RNAs (siRNAs). Specifically, the recent observations by both our groups that siRNAs can silence target genes at the level of the chromatin in mammalian cells. We discuss here siRNA mediated transcriptional gene silencing and directed DNA methylation as well as the putative mechanism involved in human cells. Undoubtedly, the ramifications from this paradigm shift of RNA regulating the expression of the gene are immeasurable both therapeutically (i.e., directed control of a genes expression) and biologically in understanding the evolution of the cell.