Overexpression of the human epidermal growth factor receptor 2 (HER2) is identified in approximately 25- 30% of breast cancers and indicates a poor prognosis. Trastuzumab, the anti-HER2 monoclonal antibody (mAb), has shown significant clinical effects selectively in HER2-overexpressing metastatic breast cancer (MBC) with improved overall survival and reduced recurrent risk. However, there is an urgent need to develop new strategies to overcome innate and acquired trastuzumab resistance, which has increasingly occurred. Recently, an increased understanding of mechanisms of trastuzumab resistance significantly promotes the development of novel targeted therapies for trastuzumab refractory disease. It is believed that aberrant activations of several signaling pathways involving the human epidermal growth factor receptor (EGFR/HER) family, phosphoinositide 3 kinase/Akt (PI3K/Akt) pathway, and vascular endothelial growth factor (VEGF) family, contribute to the development of trastuzumab resistance. Novel agents that target these relevant signal pathways provide some potential solutions, such as tyrosine kinase inhibitors (TKIs) and mAbs. HER2 is also recognized as an immunotherapeutic target. The failure to induce immune-mediated antitumor response is another important reason for trastuzumab resistance. Strategies to boost T cell-mediated immune responses specific to HER2 including HER2 vaccines and bispecific antibodies (bsAbs) could be developed as a promising way to prevent relapse or combat trastuzumab resistance. In this review, the emerging data from preclinical and clinical studies related to these novel therapies will be discussed.