Breast cancer is the most common malignancy among U.S. women, with more than 200,000 new cases diagnosed annually. In the U.S., mortality from breast cancer has declined in recent years as a result of more widespread screening, leading to earlier detection, as well as advances in the adjuvant treatment of early-stage disease. It is widely accepted that the appropriate use of adjuvant chemotherapy and endocrine therapy improves the disease-free and overall survival of patients with early-stage breast cancer. It is, therefore, standard clinical practice to administer adjuvant systemic therapy to patients with node-positive and high-risk, node-negative breast cancer. There remain, however, many controversies in the primary systemic therapy of breast cancer, which are discussed in this review.