HER2 positivity can be detected early in breast cancer development and is associated with a poor outcome. Primary systemic therapy with trastuzumab (Herceptin; F. Hoffmann-La Roche, Basel, Switzerland) in combination with taxanes and other cytotoxic agents has been studied in phase II clinical trials in women with HER2-positive breast cancer. These combinations have achieved pathologic complete response rates of 12% to 42% and clinical complete response rates of 30% to 67%. These results compare favorably with those of primary systemic therapy using standard combinations in patients with unselected (HER2-positive or -negative) breast cancer. Consequently, larger studies are in progress in which trastuzumab is administered before surgery in combination with chemotherapy. Trastuzumab is continued as monotherapy afterward to complete 1 year of treatment or until disease progression. These studies aim to provide further proof of the clinical benefits associated with trastuzumab as primary systemic therapy. They will also investigate the molecular determinants of sensitivity and resistance. In addition, four major randomized trials, in more than 13,500 patients, are investigating the impact of adding trastuzumab to standard adjuvant therapy. Planned interim cardiac safety analyses have been passed without concerns. Recruitment to these studies has either recently been completed or continues as planned. Together, this extensive program, which includes analysis of predictive molecular and pathologic makers, will establish the efficacy, safety, and role of trastuzumab in early breast cancer.