Cytotoxic chemotherapy with doxorubicin in combination with ifosfamide or dacarbazine, or gemcitabine in combination with docetaxel, continues to be the mainstay of treatment of metastatic soft-tissue sarcomas. A goal-oriented approach that includes careful consideration of histology, performance status, sites of disease, patient goals, and intent of treatment is vital to the formulation of an effective treatment plan. Both single-agent and combination chemotherapy regimens are available and should be chosen carefully to fit the clinical situation and patient goals. In patients with localized soft-tissue sarcoma who have a high likelihood of recurrent disease, systemic therapy should be strongly considered. The ability to demonstrate efficacy in the neoadjuvant setting may help avoid unnecessary treatment-related toxicity in patients with poor response and maximize recurrence-free survival in patients who do demonstrate an excellent response to therapy.