The human epidermal growth factor receptor-2 (HER2) is overexpressed and/or amplified in up to 25% of breast cancer patients, and this feature is associated with an aggressive phenotype, high recurrence rate and reduced survival. Until recently, combination chemotherapy (with or without endocrine therapy) was the only effective adjuvant treatment for HER2-positive patients. Trastuzumab is a monoclonal antibody directed against the HER2 extracellular domain, and five recent adjuvant breast cancer trials have demonstrated an astonishing and highly reproducible benefit in halving the recurrence rate and reducing mortality in patients with this phenotype. Many questions related to trastuzumab use in the adjuvant setting still remain; these include the optimum timing and duration of treatment, trastuzumab use with taxanes and radiotherapy, its role in small node-negative tumors, the optimum chemotherapy regimens and cost-effectiveness. This Review outlines the five adjuvant trastuzumab studies and discusses the controversies and challenges that have emerged for both the clinician and healthcare authorities worldwide as a consequence of the results from these trials.