The past 2 decades of systemic therapy for breast cancer have been a period of monumental change, in terms of both theory and technology. Adjuvant therapy developed from two strands of research--one in systemic chemotherapy and one in hormonal therapy--both of which were aided by the application of higher statistical methodology to clinical trials. The agent with the single greatest public health impact in oncology has been tamoxifen, but problems with tamoxifen therapy led to the development of the aromatase inhibitors, and further research led to the use of hormonal therapy in a chemopreventive capacity. The evolution of systemic chemotherapy for breast cancer has been an interplay between theory-driven approaches and new agents. By the late 1980s, accumulating data revealed that overexpression of HER2 (erbB2) played an important role in a substantial portion of breast cancers, which prompted the development of trastuzumab (Herceptin), an agent targeting HER2-positive disease. Determining HER2 status proved essential to assessing patient eligibility for trastuzumab therapy. Decoding of the human genome and application of bioinformatics further revolutionized the possibilities in breast cancer treatment.