Growth and proliferation responses mediated by the ErbB family of receptor tyrosine kinases (TKs) are often dysregulated in breast cancer, resulting in an aggressive course of disease and, historically, a poorer prognosis. The inhibition of ErbB-mediated signaling using recently developed monoclonal antibodies and small-molecule TK inhibitors has resulted in significant clinical benefit for patients with this tumor phenotype in the metastatic and adjuvant settings. However, many ErbB2-positive cancers exhibit intrinsic resistance, and the widespread development of acquired resistance to ErbB-targeted agents remains a substantial clinical problem. There are many potential mechanisms for resistance to this type of therapy, including the formation of alternative ErbB signaling complexes and crosstalk with other pathways. The simultaneous inhibition of multiple ErbB receptors and/or components of other signal cascades could therefore provide new strategies to circumvent the resistance mechanisms that often accompany ErbB-targeted approaches. In addition, regimens using combinations of targeted agents or those that incorporate existing cytotoxic drugs are continually being tested for their ability to improve responses and treat patients who have become refractory to previous therapies. Large, international collaborative efforts at designing and conducting studies to optimize treatment options for patients with ErbB2-positive breast cancer are ongoing, and careful review of data from these trials will improve tailoring of these modern therapeutic strategies.