Breast cancer is a global public health burden with more than one million new diagnoses worldwide each year. As a significant proportion of women with early-stage breast cancer experience a relapse and metastatic breast cancer is generally incurable, therapeutic innovations are ongoing. One notable innovation in recent decades has been the identification of a subset of breast cancers that overexpress the transmembrane glycoprotein human epidermal growth factor receptor 2 (HER2) and the consequent development of HER2-targeted therapy. Given the significant benefits demonstrated with the HER2-targeted monoclonal antibody, trastuzumab, in the adjuvant and metastatic settings, investigators have endeavored to develop novel mechanisms for disrupting HER2-mediated signaling. Lapatinib, an orally available HER1- and HER2-targeted tyrosine kinase inhibitor, represents one such notable innovation. Lapatinib is currently being evaluated in both the adjuvant and metastatic settings and was recently approved by the United States Food and Drug Administration in combination with capecitabine, for the treatment of women with HER2-positive, pretreated, metastatic breast cancer. However, the ideal strategy for incorporating novel HER2-targeted agents, including lapatinib, into existing management paradigms is uncertain.