Trastuzumab has had a major impact in the treatment of HER2-positive metastatic breast cancer. In combination with chemotherapy, trastuzumab provides significant clinical benefit in terms of increased response rate and extended survival compared with chemotherapy alone in patients with HER2-positive advanced breast cancer. Trastuzumab also has therapeutic activity as monotherapy in the front-line management of HER2-overexpressed or HER2-amplified metastatic breast cancer. Given its proven efficacy in the metastatic setting, the combination and sequential use of trastuzumab with adjuvant and neoadjuvant chemotherapy are the focus of several ongoing clinical studies. In this review, the design of the four major phase III multicenter adjuvant trastuzumab trials will be described and their major differences highlighted. Because therapy with trastuzumab has been associated with cardiac toxicity, especially with prior or concurrent anthracyclines, the evaluation of cardiac dysfunction in the adjuvant trial setting is also a priority. For now, the use of trastuzumab as adjuvant therapy is still investigational, but its integration has tremendous potential to improve treatment outcomes in patients with primary breast cancer.