Sarcomas are a rare, heterogeneous group of malignant tumors of the bone or soft tissue. Although historically intended for the pharmaceutical treatment of microbes, today chemotherapy is used in orthopaedic oncology and is arguably the primary reason for improved survivorship. Agents such as anthracyclines (eg, doxorubicin), alkylating agents (eg, cyclophosphamide, ifosfamide), antimetabolites (eg, methotrexate), topoisomerase inhibitors (eg, etoposide [VP-16]), vinca alkaloids (eg, vincristine), and cytotoxic antibiotics (eg, actinomycin D) are used in various combinations to manage different types of tumors. Side effects are common and range from mild to severe. The effectiveness of the chemotherapy regimen correlates with the extent of tumor necrosis.