EDITORIAL survival (PFS) initially observed with the bevacizumab and chemotherapy combination in patients with metastatic colorectal cancer was short lived. After a longer assessment period worse overall survival was observed in patients receiving the combination treatment, however, the reason for this has not been established and is likely to be complex. Should ‘rebound’effects be tested in all animal models? If the answer is yes, then continued drug dosing and assessment of host responses to therapy (with appropriate controls) would be required before clinical development commences. This would lengthen the time before a drug is tested in the clinic but should ultimately improve drug attrition rates and help identify mechanisms of resistance. The ‘rebound’effect also has implications for the end points used in phase II testing, as current end points might not be long enough to detect a relevant clinical change despite initial promising results. Moreover, high levels of drug discontinuation and dose reduction can occur even in clinical situations when antiangiogenic agents have been beneficial, such as the treatment of renal cell carcinoma. Drugs are usually tested as monotherapy in mouse models rather than in combination with other targeted agents; multi agent testing in animal models would bring us one step closer to representing the clinical situation. Despite the fact that animal model studies have not tested systemic metastatic disease and, therefore, do not include relevant survival-based analysis, VEGF therapy does work in the metastatic setting but not in the adjuvant setting. Clearly, the reasons why antiangiogenic drugs have proved disappointing in the adjuvant setting are more complex than suboptimal animal model testing. As the micro environment may have a greater influence for anti angiogenics than for cytotoxic agents, drugs that target multiple kinases might prove more successful. This possibility is perhaps evident for the EGFR and VEGF targeted agent sorafenib and might explain the relative success of this drug and other multityrosine kinase inhibitors in terms of drug attrition (Figure 1). Promising patient responses and PFS outcomes with antiangiogenic agents have not translated to overall survival benefits; thus, the use of PFS as a surrogate for survival is contentious. Crucial questions are why have antiangiogenic agents not delivered when the preclinical data have been so positive, and why have these agents not shown additive efficacy when used with cytotoxics? These questions are unanswered; however, David Kerr comments that the bolus administration of IFL chemotherapy with bevacizumab in the 2004 clinical trial by Hurwitz and coauthors, might have maximized intratumoral cytotoxic drug concentrations resulting in the dramatic benefits seen in this trial. Another possibility is the hypoxia—autophagy effect. In cancer cells, hypoxic conditions increase HIF1α levels inducing autophagy and angiogenesis, which might explain why rebound effects are seen with antiangiogenic drugs. Unfortunately, there are no predictive biomarkers for bevacizumab; VEGF is not a biomarker of bevacizumab efficacy and it is not known how well VEGF levels correlate with its activity. For the cancer field to move forward, animal models more representative of the clinical situation should be used, even if this considerably lengthens the time it takes for drugs to reach phase III testing. Of equal importance is the identification and validation of drug molecular targets. Once we get this right we might see lower drug attrition rates. doi: 10.1038/nrclinonc. 2011.34