Over the last few years it has become increasingly apparent that RNA is involved in various forms of gene regulation. While much emphasis has been placed on the role of small non-coding RNAs in post-transcriptional modes of gene regulation it has become apparent that a far more complex scenario exists. Recent observations insinuate a paradigm whereby non-coding RNAs are operative effector molecules in the transcriptional regulation of endogenous gene expression. These observations support a route for how epigenetic gene silencing is directed, maintained and passed on as epigenetic memory in human cells. This perspective will highlight the endogenous effector RNAs and mechanism of action whereby non-coding RNAs transcriptionally regulate gene expression in human cells and discuss these recent observations in the context of human evolution.