The treatment of metastatic renal cell carcinoma has evolved from an era dominated by immune modulation to an era of antiangiogenesis agents. Blockade of vascular endothelial growth factor-mediated pathways and mammalian target of rapamycin pathways has accounted for most of these gains. Although these agents have offered dramatic improvements in survival for kidney cancer patients, resistance inevitably occurs, and new classes of agents are needed to continue to improve outcomes in this setting. We discuss several alternative pathways of angiogenesis, which are being investigated as targets to overcome treatment resistance, including angiopoietin family proteins, fibroblast growth factor, platelet-derived growth factor, and vascular disrupting agents.