Over the past 2 decades, there has been an extraordinary progress in the regimens developed for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Trastuzumab, pertuzumab, lapatinib, and ado-trastuzumab emtansine (T-DM1) are commonly recommended anti-HER2 target agents by the U.S. Food and Drug Administration. This review summarizes the most significant and updated research on clinical scenarios related to HER2-positive breast cancer management in order to revise the guidelines of everyday clinical practices. In this article, we present the data on anti-HER2 clinical research of neoadjuvant, adjuvant, and metastatic studies from the past 2 decades. We also highlight some of the promising strategies that should be critically considered. Lastly, this review lists some of the ongoing clinical trials, findings of which may soon be available.