It is clear that tumor cells do not act alone but in close interaction with the extracellular matrix and with stromal cells in the tumor microenvironment (TME). As our understanding of tumor cell–stroma interactions increased over the last two decades, significant efforts have been made to develop agents that interfere with these interactions. Here, we discuss four different therapeutic strategies that target the TME, focusing on agents that are at the most advanced stage of preclinical or clinical development. We end this review by outlining some of the lessons we have learned so far from the development of TME-targeting agents. Cancer Res; 73(16); 4965–77. ©2013 AACR.