Could a rational, hypothesis-driven and well-tolerated therapy drive tumor progression? This scenario can be foreseen for antiangiogenic therapy, despite it is one of the most elegant anticancer strategies. Antiangiogenic agents inhibit growth of endothelial cells resulting in tumor hypoxia and starvation which in turn inhibit tumor growth. On the other hand, it is known that hypoxia selects for a highly aggressive and metastatic cancer and is associated with unfavorable prognosis. This review attempts to reconcile these opposite notions and to revisit the thesis that antiangiogenic therapy is "resistant to resistance". The latter logical paradigm is based on the notion that endothelial cells cannot become drug resistant. Although endothelial cells may not acquire drug-resistance, cancer cells can acquire hypoxia-resistance which is also associated with the resistance to growth arrest and apoptosis as well as high metastatic potentials. Hypoxia-inducible factor (HIF-1) renders cells capable of surviving hypoxia and stimulating endothelial growth. Disruption of the HIF-1 pathway inhibits tumor growth, indicating HIF-1 as a potential anticancer target. Furthermore, inhibition of HIF-1 is a mechanism-based antiangiogenic strategy because it is the HIF-mediated response that drives tumor angiogenesis. Pharmacological approaches to HIF-1 inhibition are discussed.