When first conceived, antiangiogenic therapy for cancer offered the possibility of universal efficacy, low toxicity, and little possibility of resistance. Blockade of the vascular endothelial growth factor (VEGF) pathway has yielded the most promising results both in animal models and in patients. However, resistance to VEGF blockade has been found even when given in combination with chemotherapy or other antiangiogenic agents. This resistance is associated with remodeled vasculature and with increased expression of angiogenic factors, such as PDGF-B and angiopoietin-1, which may contribute to vessel stabilization. Future efforts must be directed towards the identification of factors associated with vascular remodeling in order to improve the efficacy of antiangiogenic therapy.