Combination treatment with chemotherapy and trastuzumab is now standard therapy for the first-line treatment of women with HER2-overexpressing metastatic breast cancer. Combination therapy with trastuzumab has been shown to increase response rates, time to progression, quality of life, and overall survival for such patients. Several combination regimens have been developed, and newer combination regimens have recently been reported and are being studied in ongoing clinical trials. Newer trastuzumab-based regimens include triplet combinations with taxanes and platinum salts and regimens combining other innovative therapies. Among the increasing array of available combinations, several have proven appropriate for first-line therapy. To date, the optimal combination region has not been defined. Moreover, several questions remain regarding best scheduling, treatment duration, and use of trastuzumab at disease progression. This review briefly outlines the evolving role of trastuzumab in the treatment of HER2-overexpressing metastatic breast cancer.