Standard treatment of large intermediate- and high-grade extremity soft tissue sarcoma (ESTS) typically includes wide excision and radiation therapy. Many patients do well with this approach, but for those with unfavorable features, risk for distant recurrence and, ultimately, mortality can exceed 50%. Unfortunately, universally accepted data elucidating effective treatments to prevent recurrences and improve survival for such high-risk patients are lacking. Accordingly, opinions about the appropriate role of systemic therapy for patients with high-risk localized ESTS vary. This article reviews the current literature pertaining to neoadjuvant chemotherapy, concurrent chemoradiation, and adjuvant chemotherapy for high-risk ESTS. All of these approaches are feasible and reasonable to consider. Ultimately, the decision to incorporate chemotherapy into the treatment regimen is best reached by discussion among an experienced multidisciplinary sarcoma team and should be tailored to the individual patient risk profile.