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At the present time, there is not a standard regimen in upfront metastatic setting for breast cancer. A wide variety of regimens which includes anthracyclines, taxanes, gemcitabine or capecitabine are currently used, however, there is evidence to support the use of many of these drugs in early breast cancer and consequently limiting their use in first line treatment. The aim of this review is to evaluate every randomized phase III trials conducted in first line metastatic breast cancer. For this reason, all randomized studies that evaluated the role of chemotherapy in advanced breast cancer were analyzed and classified according to their protocol design. So far, sixteen major randomized clinical trials have evaluated the role of chemotherapy as front line in metastatic breast cancer. Some of them have analyzed a different anthracyclines-based regimen as the control arm versus new combinations or new drugs. In others, the aim is to evaluate the most effective therapy after progression to an adjuvant anthracyclines-containing regimen. The suitability of the control arm, the prospective definition of patient's subgroups as well as the statistical methodology have been taken into account.