Molecular assays are a new and invaluable tool in the assessment of axillary lymph node status and metastatic potential of breast cancer. Many protocols for assessing the sentinel lymph node (SLN) status have been developed based on cytology and/or histology, showing that the rate of detection of metastasis increases with the number of histologic sections examined and with use of immunohistochemical staining in addition to conventional Hematoxylin & Eosin staining. However, full standardization of protocols for this procedure has not been achieved. Further attempts to increase sensitivity and specificity of sentinel node analysis include molecular biology-based techniques such as the real-time polymerase chain reaction (RT-PCR) and, more recently, one step nucleic acid amplification (OSNA). The latter technique, that has sensitivity close to 100% and extremely high specificity along with good reproducibility, allows analysis of the SLN in full with an intraoperative procedure in approximately 30 minutes. This highly standardized method permits to compare results between groups and predicts the probability of involvement of the remaining axillary lymph nodes based on the total tumor load of the SLN(s). Results of multicenter clinical trials suggest that OSNA allows a better personalization of patients' care based on the results of SLN analysis, because it offers criteria to select patient with metastatic SLN who will not receive additional benefit from axillary clearance. Due to the current controversy on the best treatment of the axilla after a positive SLN, the SLN copy number of CK19 mRNA can have a high impact on therapeutic decisions in this group of patients. Breast cancer is a highly heterogeneous group of diseases, characterized by remarkable differences in the histopathological features, response to treatment and clinical outcome. Most of the clinical and translational research efforts during the last decades aimed at identifying markers that would allow to predict the metastatic potential of early breast cancer, and hence to assess accurately its prognosis and to inform the choice of adjuvant systemic treatments. It is now clear that neoplastic transformation, tumor progression and response to treatment are driven and accompanied by the deregulated expression of hundred or thousand genes, whose status cannot be assessed by the currently established histopathological and immunohistochemical approach. The new molecular assays have elicited a great deal of expectations, and for the most part they have been enthusiastically welcomed as potentially offering new chances for a better and more personalized care of the patients. Many, however, are still reluctant to consider these assays ready for use in the clinical practice, and keep waiting for a confirmatory evidence of their utility when the results of ongoing clinical trials will be mature.