The use of primary systemic (neoadjuvant) therapy has become widespread in the treatment of patients with locally advanced and operable breast cancer. The utilization of this therapeutic approach provides several advantages. By monitoring changes in the dimension of the tumor, efficacy can be evaluated or assessed in vivo; unnecessary toxicity can be avoided by allowing the physician to discontinue ineffective therapy. Furthermore, downstaging of a tumor through primary therapy may allow for breast-conserving surgery in patients with large operable breast cancer and render inoperable tumors resectable. Also, the use of primary therapy can provide a pathological complete response, which correlates with prolonged periods of remission. Treatment with FAC (5-fluorouracil/doxorubicin/cyclophosphamide) has proven to be effective as neoadjuvant therapy in locally advanced breast cancer in several trials. More recently, the integration of taxanes into primary therapy regimens has been explored with promising results. Studies have suggested that the use of primary therapy, particularly the use of FAC, should perhaps become the standard in patients with locally advanced disease. The history of clinical trials focusing on primary therapy in breast cancer at the M. D. Anderson Cancer Center will be reviewed.