Human epidermal growth factor receptor 2-positive (HER2+) breast cancers, which account for 25%-30% of breast cancers, are characterized by an aggressive course and a high propensity for recurrence in the 4 years following diagnosis. The use of trastuzumab-based chemotherapy in the adjuvant setting has markedly improved the outcome for patients with early stage HER2+ breast cancer. Likewise the use of trastuzumab in combination with chemotherapy in patients with metastatic HER2+ breast cancers has prolonged survival, with current expected median survival of about 3 years. Despite these major improvements in outcome, approximately 10% of patients develop a distant recurrence following adjuvant trastuzumab-based chemotherapy, and all patients with metastatic disease eventually develop disease progression. Known mechanisms of resistance to trastuzumab include increased signaling through upstream growth factors, phosphatase and tensin (PTEN) deficiency and alterations of the HER2 receptor. Many of these mechanisms are being targeted in the clinic in an attempt to improve outcome for patients with HER2+ breast cancers. The phosphatidylinositol 3-kinase (PI3K) pathway plays a key role in trastuzumab-resistance, through these and other mechanisms, and represents a logical target for drug development for trastuzumab-resistant breast cancers. The use of mammalian target of rapamycin (mTOR) inhibition has been demonstrated to potentially reverse resistance to trastuzumab in patients with HER2+, metastatic breast cancers. Phase I and II trials have produced encouraging results when the mTOR inhibitor, everolimus, was combined with trastuzumab with or without chemotherapy, in patients with trastuzumab-resistant HER2+ metastatic breast cancer. These results are being confirmed in ongoing phase III trials in the first-line and trastuzumab-resistant settings. The mechanism of how mTOR inhibitors reverse resistance to trastuzumab remains largely unexplained. Other agents targeting the PI3K pathway in trastuzumab-resistant breast cancers are in early phase clinical trials.