Epigenetic silencing of tumor suppressor gene promoters is one of the most common observations found in cancer. Despite the plethora of observed epigenetically silenced cancer related genes little is known about what is guiding the silencing to these particular loci. Two recent articles suggest that long antisense non-coding RNAs function as epigenetic regulators of transcription in human cells. These reports, along with previous observations that small antisense non-coding RNAs can epigenetically regulate transcription, imply that long antisense non-coding RNAs function as endogenous transcriptional regulatory RNAs in humans. Mechanistically, these long antisense non-coding RNAs may be involved in maintaining balanced transcription at bidirectionally transcribed loci as a method to modulate gene expression according to the selective pressures placed on the cell. The loss of this intricate bidirectional RNA based regulatory network can result in overt epigenetic silencing of gene expression. In the case of tumor suppressor genes this silencing can lead to the loss of cellular regulation and be a contributing factor in cancer. This perspective will highlight the endogenous effector RNAs and mechanism of action whereby long antisense non-coding RNAs transcriptionally regulate gene expression in human cells.