Operable breast cancer with histologically positive axillary lymph nodes has been subjected to a number of prospective randomized trials with multimodal therapy in Milan since 1973. Available results indicate that the scientific and biological hypotheses that formed the basis of multimodal therapy were correct. In fact, five years after radical mastectomy, women who had received adjuvant chemotherapy with cyclophosphamide, Methotrexate and fluorouracil (CMF) showed significant improvement in relapse-free and total survival rates. The results were related to the level of drug administered as well as to the number of axillary nodes, but not to menopausal or estrogen receptor status. Future analyses will better define the optimal duration of CMF chemotherapy (12 vs. 6 cycles) as well as the efficacy of sequential noncross-resistant regimens.