While historically breast cancer has been treated with primary surgery followed by adjuvant therapy, the delivery of systemic therapy in the neoadjuvant setting has become increasingly common, especially for triple-negative and HER2-positive breast cancer. The initial motivations for pursuing neoadjuvant chemotherapy (NAC) were decreasing the tumor burden in the breast and axilla to enable de-escalation of surgery, and use the strategy to advance drug development. While these remain of interest, recent trials have additionally demonstrated survival advantages from escalation of systemic treatment in patients with residual disease, and new studies are testing de-escalation of systemic therapy based on pathologic response. Thus, response information to NAC has become pivotal to guide adjuvant treatment recommendations, and has resulted in NAC being the preferred approach for most HER2-positive and triple-negative breast cancers. Herein, we review select landmark trials that have paved the way for the use of chemotherapy in the neoadjuvant setting for breast cancer.