Emerging evidence suggests that components of the small RNAs pathway interact with chromatin to regulate nuclear events, such as gene transcription. However, it has recently been reported that in some cases, gene transcription regulation by cellular miRNAs can occur via targeting the TATA-box motif without altering epigenetic modifications. This observation supports the notion that multiple mechanisms of miRNA-based transcriptional regulation exist, enhancing our understanding of the complexity of small RNA-mediated gene regulatory pathways. Here, we remark that miRNA-mediated transcriptional modulation, through the TATA-box motif, may be a synergistic approach for transcriptional control.