The group of soft tissue sarcomas in adult patients is a heterogeneous group with more than 40 different subtypes. While local treatment remains the mainstay for localized disease, systemic chemotherapy can importantly contribute in the treatment of advanced soft tissue sarcoma. For patients with metastatic disease, chemotherapy is a palliative treatment in the vast majority of the cases. In this setting, toxicity should not outweigh the potential benefits resulting from chemotherapy. In patients with locally advanced disease too extensive for local treatment, systemic chemotherapy can contribute to cure, provided that tumor shrinkage renders subsequent optimal local treatment possible. In these cases, chemotherapeutic regimens yielding the highest response rates achievable should be used. In the last decades, several randomized studies have aimed to determine whether combination regimens yield benefit over single-agent treatment in terms of response rate and overall survival. This review addresses the current available data on chemotherapy for adult patients with soft tissue sarcoma, excluding gastrointestinal stromal tumor, the Ewing-like sarcomas, and other small blue round cell tumors. In addition, it is increasingly recognized that future research in soft tissue sarcoma should focus on the identification of tumor factors that can serve as targets for treatment and that the diverse tumor subtypes should be analyzed separately for their sensitivity to systemic treatment. This review also focuses on these and other strategies that will hopefully lead to better out comes in this disease entity in the near future.