There is a markedly increasing contrast between the current refinement of nosologic classification of sarcoma integrating molecular typing with a growing number of subtypes and the usually standardized approach proposed in clinical practice guidelines for both local and systemic treatment. Although gastrointestinal stromal tumor (GIST), dermatofibrosarcoma protuberans, and a few other subtypes now have specific therapeutic strategies, the majority of sarcomas are still lumped together in clinical trials investigating novel therapeutic options. These trials may not provide sufficient information to guide routine clinical practice. Proof-of-concept trials exploring a targeted agent in a selected molecular subtype, randomized phase II trials, and trials focusing on histologic subtypes-all integrating translational research and aiming to identify the mechanisms of sensitivity and resistance to the treatment-are needed. This paper discusses the limitations of previous clinical trial designs to guide clinical practice in this complex context.