For patients with locally advanced breast cancer, mastectomy and/or radiation therapy achieve poor survival rates. However, the addition of cytotoxic chemotherapy optimizes outcome by treating micrometastases that are present at diagnosis. Current recommendations specify maximum doses of systemic therapy, preferably a doxorubicin-containing regimen, prior to local therapy with radiation and/or surgery. The authors review randomized studies of chemotherapy, radiation, and various combinations given pre- or postoperatively, as well as nonrandomized studies using combination chemotherapy regimens. They also discuss the possible future use of high-dose chemotherapy with autologous bone marrow rescue and the potential of manipulating growth factors which regulate breast cancer.