Breast cancer is a frequently occurring malignancy in women. Immunologically, breast cancers can be classified into four subtypes depending on the types of receptors present and their expression profiles. These are estrogen positive, progesterone positive, human epidermal growth factor receptor type 2 (HER2) positive, and triple-negative as identified by immunohistochemistry. This classification is the basis of response to treatment, prognosis, and survival. With the identification of HER2 receptor overexpression, targeted therapies with anti-HER2 agents have been developed. The first-line therapy approved for HER2 positive tumors is trastuzumab and pertuzumab linked to taxane and further treatment with an antibody-drug conjugate to achieve satisfactory outcomes. Tyrosine kinase overexpression can be treated with lapatinib, which has also been approved for improving survival and is used in combination with capecitabine. Acquired resistance in HER2 positive tumors is shown in many cases due to genetic or epigenetic modifications. Therefore, it is very important to plan therapeutic strategies and design effective treatment approaches. For a long time, only two agents, trastuzumab and lapatinib, have been approved by the Food and Drug Administration (FDA) for the treatment of HER2 positive breast cancers. There has been no appropriate treatment for trastuzumab resistance and its failure to reduce tumor growth. Lapatinib was approved by the FDA in 2007 for HER2 positive breast cancer. Three existing therapy options after trastuzumab resistance was proposed by clinicians: continuation of trastuzumab, starting therapy with lapatinib, and the synergistic use of trastuzumab and lapatinib. There have been several effective therapies proposed for HER2 positive breast cancers in correlation with clinical trials. Discovering the mechanisms of trastuzumab resistance would increase its response to therapy and better clinical outcome. Clinicians are being continuously challenged by the resistance mechanisms and bioavailability of the drugs in the treatment of metastatic breast cancers. The addition of new drugs to the chemotherapeutic regimen increases the complexity, burden of side effects, and chances of relapse. Novel anti-HER2 agents have been directed towards therapy making a major paradigm shift.