The Nek2 and Plk4 kinases serve as crucial regulators of mitotic processes such as the centrosome duplication cycle and spindle assembly. Deregulation of these processes can trigger chromosome instability and aneuploidy, which are hallmarks of many solid tumors, including breast cancer. Emerging data from the literature illustrated various functions of Nek2 in breast cancer models, with compelling evidence of its prognostic value in breast tumors. The two kinases control distinct steps in the centrosome-centriole cycle and their dysregulation lead to centrosome amplification, marked by the presence of more than two centrosomes within the cell. We found single or composite overexpression of these kinases in breast tumor samples, regardless of subtype, which strongly associated with poor prognosis. Interestingly, in a panel of established cell lines, both kinases are highly expressed in Her2-positive breast cancer cells exhibiting centrosome amplification and trastuzumab resistance. In summary, it appears that Nek2 and Plk4 might synergize to promote breast tumorigenesis and may also be involved in tamoxifen and trastuzumab resistance.