The management of HER2-positive metastatic breast cancer, a disease renowned for its aggressive natural history, has been revolutionized by the introduction of trastuzumab. Indeed, outcomes for patients with HER2-positive advanced breast cancer are now equivalent to, if not better than, those of their HER2-negative counterparts. Since the pivotal registration trial, a wealth of new clinical data has emerged regarding the use of trastuzumab in a variety of clinical contexts - adding to the evidence but also highlighting areas of uncertainly and debate. These include the optimal partner chemotherapy(ies) to trastuzumab; the effectiveness of combining trastuzumab with endocrine therapy; the benefits of continuing trastuzumab after progression on a trastuzumab-containing regimen; and the role of trastuzumab in locally advanced and inflammatory breast cancer. In this paper we review major clinical trials addressing these questions, clinical recommendations that can be made as a result, and the strength of evidence that supports them. Finally, we identify areas of ongoing uncertainty, and propose recommendations for future research in this field.