Despite extensive research efforts over the past two decades to identify effective agents for the treatment of soft tissue sarcomas, few agents are available, and with modest utility. There is a high unmet medical need to develop novel therapies for the treatment of patients with soft tissue sarcomas. Clinical trials for soft tissue sarcomas should be optimally designed, and it is crucial that they identify and define the desired clinical outcome. Survival is often the ultimate endpoint; however, physiological and biological markers are often used to predict the potential therapeutic benefit of a new agent. These endpoints can be easily measured, but can lead to false-positive results and do not take into account the complicated nature of soft tissue sarcomas. Alternative endpoints that are currently being evaluated include the progression-free survival rate, time to progression, tumor growth rate, and progression arrest rate. This article discusses some of the limitations of current endpoint criteria and potential endpoint criteria that could be used to evaluate treatment options for patients with soft tissue sarcomas.