Soft tissue sarcoma is a malignant connective tissue tumor that may arise anywhere in the body and from diverse mesenchymal elements. Its incidence is approximately 30 per million persons. The majority of patients with soft tissue sarcoma present with potentially life-threatening disease, and complete resection to obtain specimen margins free of tumor and radiation offer the best chance for local disease control. The risk of relapse and death from disease rises with increasing tumor stage, grade, and size. Adjuvant chemotherapy has been studied as a means to decrease the risk for disease recurrence in patients with localized soft tissue sarcoma at diagnosis, but the majority of trials reported on have been hampered by patient heterogeneity, low patient accrual, and short follow-up. Meta-analysis and reviews of institutional large series, in efforts to overcome some of the limitations, suggest that doxorubicin with ifosfamide reduces the risk for sarcoma recurrence and death in selected patients with high-grade, large, and chemotherapy-sensitive sarcoma subtypes to a clinically meaningful degree. In multiple analyses, patients with high-risk soft tissue sarcoma treated with chemotherapy have a >10% absolute lower risk for disease recurrence and longer disease-specific survival than patients treated without chemotherapy. In the absence of conclusive results from an adequately powered, randomized, controlled clinical trial, the available data support the use of chemotherapy in the management of high-risk, localized, soft tissue sarcoma.