The discovery of human epidermal growth factor receptor 2 (HER2) and its role in the biology of breast cancer, and the subsequent development of HER2-targeted therapies, have dramatically improved clinical outcomes for millions of women with early-stage and advanced HER2-positive breast cancer. This review discusses the treatment of primary, nonmetastatic HER2-positive breast cancer in the adjuvant and neoadjuvant settings--settings in which tremendous progress has been made. Novel approaches, including the use of combinations of HER2-targeted therapies, are examined. Future challenges include refining such treatments, reducing toxicity in those who have low-risk disease, and simultaneously developing innovative therapies for patients who remain at high risk for relapse with existing treatment options.