Non-GIST soft tissue sarcomas are a heterogeneous grouping of mesenchymal tumors that comprise less than 1% of adult malignancies. Treatment continues to be based on cytotoxic chemotherapy regimens. However, characterization of the molecular pathway deregulations that drive these tumors has led to the emergence of more customized treatment options. In this review, we focus on the multitude of molecular inhibitors targeting angiogenesis and cell cycle pathways being tested in clinical trials. J. Surg. Oncol. 2015 111:632–640. © 2014 Wiley Periodicals, Inc.