Structurally, protein kinase CK2 consists of two catalytic subunits (α and α') and two regulatory subunits (β), which play a critical role in targeting specific CK2 substrates. Compelling evidence shows the complexity of the CK2 cellular signaling network and supports the view that this enzyme is a key component of regulatory protein kinase networks that are involved in several aspects of cancer. CK2 both activates and suppresses the expression of a number of essential oncogenes and tumor suppressors, and its expression and activity are upregulated in blood tumors and virtually all solid tumors. The prognostic significance of CK2α expression in association with various clinicopathological parameters highlighted this kinase as an adverse prognostic marker in breast cancer. In addition, several recent studies reported its implication in the regulation of the epithelial-to-mesenchymal transition (EMT), an early step in cancer invasion and metastasis. In this review, we briefly overview the contribution of CK2 to several aspects of cancer and discuss how in mammary epithelial cells, the expression of its CK2β regulatory subunit plays a critical role in maintaining an epithelial phenotype through CK2-mediated control of key EMT-related transcription factors. Importantly, decreased CK2β expression in breast tumors is correlated with inefficient phosphorylation and nuclear translocation of Snail1 and Foxc2, ultimately leading to EMT induction. This review highlights the pivotal role played by CK2β in the mammary epithelial phenotype and discusses how a modest alteration in its expression may be sufficient to induce dramatic effects facilitating the early steps in tumor cell dissemination through the coordinated regulation of two key transcription factors.