The management of metastatic breast cancer remains an important and controversial issue. The systemic therapy, comprising endocrine, cytotoxic and biological agents, can be administered sequentially or in combination. Few drugs or combinations provide a significant improvement in survival and, therefore, in the great majority of cases, treatment is given with a palliative intent. With the exception of first-line therapy, for which general agreement exists, currently there is no consensual standard of care. This review will summarize the current knowledge and outline the controversial issues related to systemic therapy of metastatic breast cancer, with emphasis on treatment tailoring. The potential role of tumor molecular profile(s) in the selection of patients that could benefit the most from each strategy/agent will be discussed.