There is strong clinical evidence that trastuzumab, a monoclonal antibody targeting the human epidermal growth factor receptor (HER) two tyrosine kinase receptor, is an important component of first-line treatment of patients with HER2-positive metastatic breast cancer. In particular the combination with taxanes and vinorelbine has been established. In the preoperative setting inclusion of trastuzumab has significantly increased the pathological complete response rate. Results from large phase III trials evaluating adjuvant therapy in HER2-positive early breast cancer indicate that the addition of trastuzumab to chemotherapy improves disease-free and overall survival. The use of lapatinib, a dual tyrosine kinase inhibitor of both HER1 and HER2, in combination with capecitabine in the second-line treatment of HER2-positive patients with metastatic breast cancer previously treated with trastuzumab has been established. There is modest, but still insufficient, support that the compound passes the blood-brain barrier. Several trials are ongoing both in the adjuvant and metastatic settings and we have to await the results of these to clarify the role of trastuzumab and lapatinib. The clinical problem of tumours developing resistance to HER2-directed therapy is becoming increasingly important. Several issues about optimal selection of patients, prevention of resistance and use of different treatment options are still unresolved. In this article, we summarise the current knowledge on clinical evidence of HER2-directed therapy and the potential mechanisms of underlying resistance, including the possible clinical implications and review new therapeutic options.