Adult-type soft tissue sarcomas (STS) are curable in roughly one half of cases. Surgery is the treatment mainstay in patients with localized STS and should be performed in centers that have specific expertise with the disease. Radiation therapy complements surgery in several cases, improving the local control. The value of adjuvant chemotherapy is still debated. There is some evidence, however, backing the notion that adjuvant chemotherapy may add to the systemic control of the disease, and thereby overall survival, in the subgroup of patients with high-risk STS. These patients are those with a high-grade, large, and deep tumor. Unfortunately, benefit is apparent when merging all data generated by several trials performed throughout decades, but it was not confirmed by the largest trials, including one that was recently reported. A confounding factor for large clinical trials is that STS are a family of 50-plus different histological subtypes. It is difficult to perform studies that focus on each of them separately, and subgroup analyses suffer from many limitations. Indeed, some histological types are more sensitive to standard chemotherapy and other are less. Furthermore, some histologies are specifically sensitive to some agents that may be completely inactive in others. A prospective, randomized trial is underway to compare standard neoadjuvant chemotherapy in high-risk STS versus a neoadjuvant regimen that is tailored to different histologies. Some rare histological subtypes (alveolar soft part sarcoma, clear cell sarcoma, extraskeletal myxoid chondrosarcoma, solitary fibrous tumor) have shown promising sensitivity to molecular target agents in the metastatic setting, but the value of these therapies in the adjuvant one has not been studied yet. It is probable that in the future the biological background of the different soft tissue sarcoma subtypes will guide the selection of therapies as well as the setting to deliver them.