Doxorubicin monotherapy is the standard first-line treatment in patients with advanced soft-tissue sarcomas. Ifosfamide still remains the standard 2nd line treatment after doxorubicin-failure. However, recent data have demonstrated that histological subtypes differ in their sensitivity to cytotoxic drugs. Therefore, gemcitabine should be considered as the best option after doxorubicin failure in leiomyosarcoma patients. Trabectedine should be used preferentially in myxoid liposarcomas and leiomyosarcomas patients whereas paclitaxel should be considered as a first or second-line treatment of choice in angiosarcoma patients. Further studies are needed in order to identify predictive factors of clinical benefit in advanced soft-tissue sarcoma patients treated with cytotoxic agents in combination or not with targeted therapies.