Breast cancer is the most common malignancy in women worldwide and remains a major cause of mortality, thus necessitating further therapeutic advancements. In breast cancer, numerous cell signaling pathways are aberrantly activated to produce the myriad phenotypes associated with malignancy; such pathways include the PI3K/ Akt/mTOR, NF-?B and JAK/STAT cascades. These pathways are highly interconnected, but one prominent lateral enhancer of each is the remarkably promiscuous kinase CK2. CK2 expression has been shown to be elevated in cancer, thus implicating it in tumorigenesis through its effects on oncogenic signaling cascades. In this study, we identify aberrant expression of CK2 subunits in human breast samples from The Cancer Genome Atlas dataset. Additionally, two specific small molecule inhibitors of CK2, CX-4945 and TBB, were used to examine the role of CK2 in two human breast cancer cell lines, MDA-MB-231 and MCF-7 cells. We show that CK2 inhibition attenuates constitutive PI3K/Akt/mTOR, NF-?B and STAT3 activation and inducible NF-?B and JAK/STAT activation and downstream transcriptional activity. CX-4945 treatment caused a range of phenotypic changes in these cell lines, including decreased viability, cell cycle arrest, apoptosis and loss of migratory capacity. Overall, these results demonstrate the tremendous potential of CK2 as a clinical target in breast cancer.