Trastuzumab is a monoclonal antibody directed against the human EGFR2 (HER2) protein that has been shown to improve survival in patients with HER2-positive breast cancer. Lapatinib is an oral small-molecule tyrosine kinase inhibitor directed against EGFR and HER2. Lapatinib therapy was shown to prolong the time to progression and increase the rate of response to capecitabine in patients who had received anthracycline-based and taxane-based chemotherapy, and whose tumors had progressed on trastuzumab. HER2 status, either gene copy number or the protein expression level, is the best predictive marker available for assessing response to trastuzumab and lapatinib. Whether the power of this predictive marker is the same in advanced and early-stage cancers is unknown. There is great interest in developing diagnostic tests that predict which patients are more likely to benefit from specific HER2-directed therapies. Novel therapeutics that will overcome resistance to trastuzumab and lapatinib are under intense clinical development. In the future, it will be important to characterize mechanisms of resistance in metastatic tumors to determine which novel targeted therapy will be most appropriate for individual patients.