In the early 1960s, breast cancer was considered to be poorly responsive to chemotherapy. However, several agents, in particular methotrexate, vincristine, 5- fluorouracil, cyclophosphamide, an alkylating agent synthesized in Germany, and prednisone were found to be active in women with metastatic breast cancer. These five drugs were then used in advanced breast cancer in a combination referred to as the “Cooper regimen” that triggered a number of studies using quadruple and quintuple chemotherapeutic drug combinations which induced response rates superior to therapy with single agents. These results led to the integration of combination chemotherapy into a combined modality approach, epitomized by modern ʻadjuvantʼ chemotherapy. A first randomized study comparing long-term postoperative single drug chemotherapy to a placebo led to improved survival in a subset of patients. Superior results were subsequently achieved with postoperative combination chemotherapy. The historical development of these approaches is described.