This paper reviews a series of sequential clinical trials at the University of Arizona Cancer Center which were designed to improve the outcome in both advanced and early breast cancer by utilizing the combination of intravenous adriamycin and oral cyclophosphamide (A-C) alone or with the addition of other agents or modalities. Our initial trial in advanced breast cancer with A-C produced an overall objective response rate of 78 % in 51 patients with advanced breast cancer without prior chemotherapy. The median duration of disease control was 12 months. Subsequent studies showed that the addition of either vincristine or the androgen, calusterone, effectively doubled the remission duration and prolonged survival. However, we learned that lower doses of adriamycin reduced the efficacy of the A-C combination (response rate 53%) although it permitted a longer duration of drug administration before reaching potentially cardiotoxic limits. Our surgical adjuvant trial with 6 months of treatment with A-C was begun in 1974. There has been only a 9% relapse rate in stage II patients thus far, with a median follow-up of close to 2 years. A subset of stage II patients who received regional radiotherapy along with A-C have not yet shown added benefit compared to the use of A-C alone. Since 1975, stage I patients have been treated with an abbreviated treatment schedule (3 courses of A-C over 9 weeks). While there have not yet been relapses in this category, much longer periods of follow-up will be required. The use of A-C (plus other drugs) has clearly provided excellent palliation and improved survival in patients with advanced or recurrent breast cancer; in our opinion it should be used as initial cytotoxic chemotherapy. The brief intensive program of A-C as a surgical adjuvant also shows considerable promise for erradicating occult micrometastases in both pre- and postmenopausal women.