The past decade has seen an explosion in discovery of small, non-coding RNAs in all organisms. As functions for many of the small RNAs have been identified, it has become increasingly clear that they are important components in regulating gene expression. A multitude of RNAs target mRNAs for regulation at the level of translation or stability, including the microRNAs in higher eukaryotes and the Hfq binding RNAs in bacteria. Other RNAs regulate transcription, such as murine B2 RNA, mammalian 7SK RNA and the bacterial 6S RNA, which will be the focus of this review. Details of 6S RNA interactions with RNA polymerase, how 6S RNA regulates transcription, and how 6S RNA function contributes to cellular survival are discussed.