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Indiana University-Purdue University Indianapolis (IUPUI) / Cancer stem cells (CSCs) are proposed to play a major role in tumor progression, metastasis, and recurrence. The Human Epidermal growth factor Receptor 2 (HER2) gene is amplified and/or its protein product overexpressed in approximately 20% of breast cancers. HER2 overexpression is associated with increased CSCs, which may explain the aggressive phenotype and increased likelihood of recurrence for HER2+ breast cancers. Telomerase is reactivated in tumor cells, including CSCs, but has limited activity in normal tissues, providing support for the use of telomerase inhibition in anti-cancer therapy. Telomerase inhibition via an antagonistic oligonucleotide, imetelstat (GRN163L), has been shown to be effective in limiting cell growth in vitro and limiting tumor growth. Moreover, we have previously shown imetelstat can decrease metastases to the lungs, leading us to question if this is due to imetelstat targeting the CSC population. In this thesis, we investigated the effects of imetelstat on CSC and non-CSC populations of HER2+ breast cancer cell lines, as well as a triple negative breast cancer cell line, which lacks HER2 overexpression. Imetelstat inhibited telomerase activity in both CSC and non-CSC subpopulations. Moreover, imetelstat treatment alone and in combination with trastuzumab significantly reduced the CSC fraction and inhibited CSC functional ability, as shown by a significant decrease in mammosphere counts and invasive potential. Tumor growth rate was slower in combination treated mice compared to either drug alone. Additionally, there was a trend toward decreased CSC marker expression in imetelstat treated xenograft cells compared to vehicle control. The decrease in CSC marker expression we observed occurred prior to and after telomere shortening, suggesting imetelstat acts on the CSC subpopulation in telomere length dependent and independent mechanisms. Our study suggests addition of imetelstat to trastuzumab may enhance the effects of HER2 inhibition therapy.