Recent genome-wide studies revealed that only 2% of the human genome encodes for proteins while as much as 80% of the genome can be transcribed. Of these non-coding transcripts, long non-coding RNAs (lncRNAs) represent the largest and most diverse class. Recently, we identified 30 potentially oncogenic lncRNAs in mouse models of human breast cancer, termed Mammary Tumor Associated RNAs (MaTARs). To functionally validate the role of MaTARs, we performed antisense knockdown experiments and observed reduced cell proliferation, invasion and/or organoid branching in a cancer-specific context. Assessing the expression of human MaTARs (hMaTARs) in TCGA data revealed that 19 hMaTARs are significantly up-regulated in breast cancer. In addition, the expression of many hMaTARs correlates with breast cancer subtype and/or hormone receptor status, indicating potential clinical relevance. We further focused on MaTAR17 and MaTAR20, as independent knockdown of these two lncRNAs lead to significant reductions in tumor cell proliferation, migration and invasion. The knockdown results were validated using MaTAR17 and MaTAR20 knockout cells, generated using the CRISPR/Cas9 system. Notably, injection of antisense oligonucleotides (ASOs) targeting MaTAR17 or MaTAR20 into a transgenic mouse model of breast cancer resulted in a significant decrease of tumor cell growth or metastasis to the lungs, respectively. Ongoing studies are investigating the molecular mechanism by which MaTAR17 and MaTAR20 function to impact cancer progression. Our results suggest that MaTARs are likely important drivers of mammary tumor progression and represent promising new therapeutic targets.