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Background: Alteration of the expression of human epidermal growth factor receptor-2 gene as an oncogenic pathway in breast cancer was first explored in the 1980'. Since then, tremendous progress has been made in treating HER2-positive breast cancer. Methods: We performed a narrative type review of the existing literature using as a starting point the PubMed database, investigated by keywords, later the search being refined and the articles that we considered relevant were selected. The approach to the topic under discussion being variable in the various studies identified convinced us of the inappropriateness of a meta-analysis. As a secondary method of analysis, we evaluated the bibliography of each of the selected studies and from this we identified other publications of interest. Results: At present, there are three major classes of FDA-approved anti-HER2 agents: monoclonal antibodies (Trastuzumab, Pertuzumab and Margetuximab), TKIs (Lapatinib, Neratinib and Tucatinib) and antibody-drug conjugates (T-DM1 and T-DXd). The treatment of HER2+ breast cancer suffered some changes in the last few years. If in 2018, after progression under first-line treatment with taxane-trastuzumab/pertuzumab and second line with T-DM1 was a big challenge, being up to the oncologist to choose from lapatinib-capecitabine, trastuzumab-lapatinib or different chemotherapeutic agents, depending on toxicities and therapies available in the country, nowadays we have a new third- and fourth-line FDA approved standard, which consists of tucatinib-trastuzumab-capecitabine and trastuzumab-deruxtecan.  Conclusion: Times are very exciting for HER2-positive disease. What differentiates novel therapies and if we do it better is both the question that we tried to give an answer to in this review of literature, but it remains at the same time a topic of discussion and a directive for analysis in the future, because we are only getting closer to an optimal version of treatment for HER2+ breast cancer, hoping that the introduction of new drugs and the establishment of new indications for old drugs will allow us to standardize the treatment of these patients.

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