Amplification of the HER2/neu gene occurs in approximately 20-25% of invasive breast cancers and is associated with poor patient outcome. The development of trastuzumab, a humanized monoclonal antibody that binds to the extracellular domain of HER2, has led to a significant improvement in outcomes of patients with HER2-positive breast cancer. However, many patients with HER2- positive metastatic breast cancer do not respond to trastuzumab, or eventually become resistant to it. In addition, approximately 15% of patients treated with trastuzumab-based therapy in the adjuvant setting relapse. In this review, we discuss the mechanisms of antitumor activity of trastuzumab, potential mechanisms contributing to its resistance, and novel therapeutic agents that may provide a means to overcome trastuzumab resistance.