Long non-coding RNAs (lncRNAs) are transcripts of a recently discovered class of genes which do not code for proteins. The ENCODE Consortium (Derrien et al 2012; www.gencodegenes.org) determined that more than two-thirds of human genes do not encode proteins; however, comparatively little remains known about lncRNA functions. Using a full-length-cDNA-based, targeted strategy (Lipovich et al 2012), we globally interrogated changes in the lncRNA transcriptome of oestrogen receptor positive human breast cancer cells following treatment with oestrogen, and identified 127 oestrogen-responsive lncRNAs. Consistent with the emerging evidence that most human lncRNA genes lack homologs outside of primates (Washietl et al 2014; Necsulea et al 2014), our evolutionary analysis revealed primate-specific lncRNAs, which arose after the prosimian split, as direct downstream targets of oestrogen signaling. We demonstrate, by using multiple functional assays (including MTT and crystal violet cell staining with automatic and confirmatory manual cell counting) to probe gain and loss of function phenotypes in two oestrogen receptor positive human breast cancer cell lines, that two primate-specific oestrogen-responsive lncRNAs identified in this study (the oestrogen-repressed lncRNA BC041455, which reduces cell viability, and the oestrogen-induced lncRNA CR593775, which increases cell viability) control cell proliferation. BC041455 also dephosphorylates ERK, demonstrating that a primate-specific lncRNA can regulate the deeply conserved MAP kinase pathway. Integrating RNAseq and deep mass spectrometric proteome analysis of the same cells before and after exposure to estrogen, we have also identified estrogen-repressed translation of a hominid-specific peptide from a primate-specific transcript of the lncRNA MMP24-AS1, building upon our discovery that specific lncRNAs are rarely and nonrandomly translated in human cells (Bánfai et al 2012) and presenting initial evidence that ectopic translation of lncRNA open reading frames into novel peptides can be hormone-dependent. The results show that oestrogen-responsive, primate-specific lncRNAs alter the proliferation and viability of human breast cancer cells. Because primate-specific lncRNAs are evolutionarily young nodes connected only by sparse edges to ancient conserved nodes (such as proteins) in networks, their therapeutic disruptions are expected to result in fewer side effects than current small-molecule-based, protein-targeting therapies. Our results should facilitate exploiting and targeting these cell viability modulating lncRNAs in post-genomic therapeutics. [ This work has been supported by the U.S. National Institutes of Health (NIH) Director’s New Innovator Award, 1DP2-CA196375, 2014-2019, to LL. ]