The hypothesis that tumor growth and metastasis is angiogenesis-dependent was 
proposed by Judah Folkman in 1971. Its major implication is that blocking 
angiogenesis could be a strategy for arresting tumor growth. This hypothesis is 
now supported by extensive experimental evidence, and hence the angiogenic 
switch and microvascular endothelial cells recruited by the tumor have emerged 
as important targets in cancer therapy. A large number of proangiogenic and 
antiangiogenic factors have been discovered. At least three angiogenesis 
inhibitors have received FDA approval in the US, with Avastin 
(anti-VEGF-antibody) also approved in 26 other countries. The recognition that 
antiangiogenic therapy is becoming the fourth therapeutic modality in addition 
to surgery, chemotherapy and radiotherapy underlines the urgent need to 
understand the systems biology of the antiangiogenic response. A particularly 
important question for cancer therapy is whether antiangiogenic therapy will 
also face the same drug resistance as one sees with other treatment modalities. 
Recently, the cellular signaling induced by the endogenous angiogenesis 
inhibitor - endostatin - was dissected revealing that the antiangiogenic 
response is characterized by a large number of individual genetic signals, which 
are highly coordinated and interdependent. The objective of this review is to 
elucidate the multifaceted nature of tumor angiogenesis, and to discuss the 
subtle but important distinctions that exist between variations in tumor 
responsiveness that evolve with antiangiogenic therapy and the classic 
resistance that frequently develops with conventional therapy. Furthermore, this 
review discusses the implications of current findings for cancer treatment and 
potential ways of overcoming or predicting tumor resistance to these agents.