Small RNA molecules, including small interfering RNA (siRNA) and micro RNA (miRNA), have rapidly emerged as important regulators of gene expression. Recent articles have demonstrated RNA mediated complex induced transcriptional gene silencing (TGS) occurring in the nucleus. Originally the small RNA mediated TGS pathway has been reported in yeast and plants, currently a number of articles strongly suggest that this newly established gene silencing mechanism is present in mammals. RNA mediated TGS has been reported for various human promoters including inhibition of tumor susceptibility genes, X-chromosome inactivation and suppression of human chemokine receptor. Small RNAs can inhibit human viral infection through the TGS pathway. Prolonged HIV-1 transcriptional gene silencing by an RNA duplex targeting a sequence located within the HIV-1 promoter has been reported initially using a susceptible adherent cell line model and recently prolonged suppression of productive HIV-1 infection in a T-cell line model has been demonstrated by a retrovirally delivered short-hairpin RNA (shRNA) targeting the same region. RNA mediated gene silencing in HIV-1 infection can induce heterochromatin (closed) structure in the promoter regions, which is consistent to those changes seen in studies of various RNA directed TGS in various human promoter regions. More recent observations suggest transcriptional activation can be induced through RNA duplexes targeting the human promoter of E-cadherin, p21 and the progesterone receptor. Although the precise mechanisms of how RNA mediated transcriptional gene silencing or activation functions has yet to be elucidated, this review describes linkage of small RNA mediated gene regulation and induction of epigenetic regulation in the promoter region in mammals.