Conventional chemotherapy can have a favorable impact on the natural history of disease for selected patients with primary high-risk bone and soft-tissue sarcomas. In particular, multidrug regimens are integral to the care of patients with the most aggressive histologies, including Ewing sarcoma, osteosarcoma, and non-pleomorphic rhabdomyosarcoma. Appropriately selected patients with high-risk, clinically localized soft-tissue sarcomas may also benefit from histology-tailored adjuvant or neoadjuvant therapy. For patients with recurrent disease, conventional chemotherapy is frequently the most appropriate first-line therapy; active drugs are discussed at length. Several new promising cytotoxic chemotherapeutic agents are currently under development, including aldoxorubicin, TH-302, and trabectedin. J. Surg. Oncol. 2015 111:622–631. © 2015 Wiley Periodicals, Inc.