Breast cancer (BrCa) is the most frequent neoplastic disease in female. A lot of efforts were done in order to make an early diagnosis, to test new regimens of chemotherapy, and to identify new targets for therapy. All these were the consequence of the high rate of specific morbidity and mortality which continue to increase. Drug resistance and escape from therapy are well documented, and are associated to low overall survival. An important step has been achieved almost two decades ago, when a new classification of BrCa has been introduced. The molecular classification was based on the gene analysis profile, and immunohistochemistry has been shown to be a good surrogate. This was a very important observation, because in this way the molecular classification can be largely applied in clinical practice, and virtually, today all labs of pathology evaluate minimum the expression of hormone receptors, HER2 and Ki67. Based on these methods, hormone therapy and treatment with trastuzumab became an efficient reality. By tradition and protocol, these methods were particularly done in specimens of primary tumors – frequently removed at the time of molecular diagnosis. Until 2010, lymph node metastasis (LNM) were really forgotten if not excluded from this evaluation. Just scattered studies have shown significant differences between the molecular profile of primary tumor, LNM and distant metastasis. Taken together, these differences account for almost 20%, and strongly influence the natural evolution of BrCa, and the response to specific therapeutic strategies. Virtually, there is a lack of large studies (if any) concerning a comparison between the primary tumor and corresponding lymph node metastasis. Discrepancies could explain, at least in part, drug resistance or hormone therapy “escape”. We have investigated a large series of patients with BrCa and LNM, applying an extended panel of markers that allow the full characterization of the molecular type in both primary tumor and LNM. We found HER2 as the most stable subtype, without significant conversion. The most unstable was luminal A subtype, associated with luminal B or even basal-like molecular subtype in the LMN. Overall, cross-match between primary tumor and corresponding LNM was found in 76% of the cases. Our data strongly support the application of immunohistochemical methods in all specimens surgically removed, because the prognosis could be worse looking only to LNM profile. This is actually a first step to personalized therapy in breast cancer.