The concept of antiangiogenic therapy in cancer treatment has led to the approval of different agents, most of them targeting the well known vascular endothelial growth factor pathway. Despite promising results in preclinical studies, the efficacy of antiangiogenic therapy in the clinical setting remains limited. Recently, awareness has emerged on resistance to antiangiogenic therapies. It has become apparent that the intricate complex interplay between tumors and stromal cells, including endothelial cells and associated mural cells, allows for escape mechanisms to arise that counteract the effects of these targeted therapeutics. Here, we review and discuss known and novel mechanisms that contribute to resistance against antiangiogenic therapy and provide an outlook to possible improvements in therapeutic approaches.