The role of targeted therapies in the treatment of women with breast cancer has been rapidly evolving. Trastuzumab, a monoclonal antibody against the human epidermal growth factor receptor 2 (her2), was the first her2-targeted therapy that clearly demonstrated a significant clinical benefit for women with her2-overexpressing metastatic breast cancer (mbc). However, in recent years it has become increasingly apparent that, when trastuzumab is used in the first-line setting in combination with chemotherapy, most women eventually develop progressive disease. Determining the treatment options available to women who have progressed while on trastuzumab therapy has been hampered by a paucity of high-quality published data. In addition, with the standard use of trastuzumab in the adjuvant setting (for eligible her2-positive patients), the role of anti-her2 agents for patients who experience a breast cancer relapse has become a clinically relevant question. This manuscript reviews current available data and outlines suggestions from a panel of Canadian oncologists about the use of trastuzumab and other her2-targeted agents in two key mbc indications: (1) Treatment for women with her2-positive mbc progressing on trastuzumab (that is, treatment beyond progression); (2) Treatment for women with her2-positive mbc recurring following adjuvant trastuzumab (that is, re-treatment). The suggestions set out here will continue to evolve as data and future trials with trastuzumab and other her2-targeted agents emerge.