Breast cancer accounts for approximately 30% of all new cancer cases each year, with an annual incidence of approximately 200,000. Additionally, almost 25% of breast cancers are noted to overexpress Her2, which is an epidermal growth factor receptor. Overexpression of Her2 has been associated with a more aggressive phenotype with decreased survival. Trastuzumab, a recombinant monoclonal antibody against the Her2 receptor, is the only FDA-approved targeted agent for treatment of Her2-overexpressing breast cancer. However, despite the great success achieved with trastuzumab, many women will either not respond or eventually progress despite trastuzumab treatment. As a result, significant efforts have been applied to finding other therapies besides trastuzumab for the treatment of Her2-positive breast cancer. Work has been directed at trying to elucidate the exact mechanism of resistance to trastuzumab and identifying ways to overcome them, at increasing the efficacy of trastuzumab by combining it with other therapeutic agents and at investigating other novel agents.