Anthracyclines were first introduced for the treatment of metastatic breast cancer in the 1970s and are still among the most active single agents for the treatment of this disease. Unfortunately, their clinical value is limited by late-onset ventricular dysfunction. Epirubicin, an anthracycline analogue, does not eliminate the risk of cardiotoxicity but is less cardiotoxic and myelotoxic than doxorubicin at equimolar doses, thereby allowing the safe administration of cumulative doses between 950 and 1000 mg/m2. The inclusion of epirubicin in combination regimens, such as fluorouracil/epirubicin/cyclophosphamide (FEC), has been shown to be safe and active as first-line treatment for metastatic breast cancer. In the past few years, new drugs, including taxanes, have shown a high level of activity as single agents in the treatment of advanced breast cancer. Doxorubicin/paclitaxel combinations have shown high overall response rates (90%) as first-line chemotherapy of advanced breast cancer; however, congestive heart failure has been reported in up to 20% of patients. Epirubicin/paclitaxel combinations have been associated with grade 3 cardiotoxicity (6%) in only one study. We report findings of a trial of combination epirubicin/paclitaxel as first-line treatment of advanced breast cancer, with overall response rates (ORRs) of 84% and a complete response (CR) rate of 19%. Achieving a CR to first-line chemotherapy for advanced breast cancer appears to predict survival, and adding an active drug with a different mechanism of action and nonoverlapping toxicity might increase the percentage of CRs. We therefore tested the feasibility and activity of 6 to 8 courses of first-line treatment with a three-drug combination (gemcitabine 1000 mg/m2 days 1 and 4, epirubicin 90 mg/m2 day 1, and paclitaxel 175 mg/ m2 over 3 hours on day 1) in a phase II study of 36 metastatic breast cancer patients. Treatment was well tolerated, with an ORR of 92% (95% confidence interval: 77.53%-98.25%) and a CR of 31%. In considering retreating patients who progress or relapse after receiving an anthracycline-/taxane-containing regimen with the same active drugs, epirubicin appears ideal in both the adjuvant and metastatic breast cancer settings.