The treatment decision for patients with metastatic breast cancer who have received anthracyclines within the course of adjuvant chemotherapy is troublesome, particularly if trastuzumab and hormonal treatment are not indicated. In the first part of this review we discuss the value of retreatment with anthracyclines, a topic that has been indirectly evaluated by retrospective studies with conflicting results and within a small phase III trial with a negative outcome. Evidence on liposomal anthracyclines is also reviewed. In the second part of the review, alternative options of first-line chemotherapy are discussed. These include taxanes as single agents, taxanes in combination with other cytotoxic drugs, combinations without anthracyclines and taxanes, and innovative treatments including target-based agents. Both the amount and the quality of evidence on these treatments are poor. Few phase III studies are available and most of them have been performed with registrative aims sponsored by the companies who own the winning drug. Beyond indications derived from such studies, there is a great need for more clinical research in this setting.