The tumor vasculature is an increasingly attractive target for development of anticancer drugs. The fundamental principle for antiangiogenic cancer therapy is based on the inhibitory effect of chemical compounds, proteins or nucleotides on tumor angiogenesis. Indeed, in almost all preclinical tumor models, antiangiogenic monotherapy with different agents shows potent effects on suppression of tumor growth. However, antiangiogenic monotherapy has barely produced any clinical benefits in cancer patients. Although in combination with chemotherapy some antiangiogenic drugs demonstrate survival improvement in patients with certain types of cancers, the overall benefits by addition of antiangiogenic drugs (ADs) to chemotherapy remain modest. The disparity of AD responses between preclinical models and clinical cancer patients has raised important issues, which include: 1) Are current animal tumor models appropriate for assessing the therapeutic efficacy of ADs for clinical development? 2) What are the key differences between mouse tumor models and human cancer patients? 3) Are anti-VEGF drugs off target in cancer patients? 4) What are alternative options for improvement of the clinical benefits of ADs? In this short review, I discuss these critical issues in relation to the clinical practice of ADs.