There is a large family of known pro-angiogenic growth factors, many of which can be expressed by a single tumor, especially in advanced stages of disease. Such redundancy, which can be amplified by hypoxia, has long been suspected as a potential cause of acquired resistance when tumors are treated with highly specific targeted antiangiogenic drugs. Definitive preclinical evidence for antiangiogenic drug evasion by alternate pathways of angiogenesis in tumor cells, likely induced by antiangiogenic drug-mediated increases in tumor hypoxia, is reported in this issue of Cancer Cell (casanovas et al.,2005); it has major implications for the development of strategies to prolong the effectiveness of antiangiogenic drugs as monotherapies, and for their use as chemosensitizing agents in combination treatment strategies.