Over 30 years ago, it was proposed that blocking new blood vessel formation would significantly inhibit solid tumor growth and hence, limit cancer progression. Efforts guided by this philosophy have resulted in a better understanding of the molecular basis of tumor angiogenesis. The first successful therapeutic to emerge from this work, an antibody (bevacizumab) targeting the vascular endothelial growth factor (VEGF), was recently approved for the treatment of colorectal cancer. Additional positive clinical data with bevacizumab in the treatment of breast and lung carcinoma have also been reported. These clinical achievements have validated the approach of anti-angiogenesis therapy for cancer and provided further confirmation for antibodies as a therapeutic class in this disease. Nevertheless, important unanswered questions with regard to preclinical and clinical results of VEGF pathway inhibitors remain. For example, preclinical models with a number of VEGF pathway inhibitors suggest that these agents would have significant clinical activity on their own; yet, clinical activity in patients with bevacizumab or other VEGF pathway inhibitors as monotherapy have been disappointing. Moreover, while bevacizumab is approved for the treatment of colorectal cancer in combination with cytotoxics, the mechanism for the benefits of this combination are still poorly understood, with a number of viable mechanisms under active experimental evaluation. The 3-8-month survival benefit in colorectal cancer patients treated with bevacizumab is a positive step forward. However, improving our understanding of the mechanism for these effects, as well as the mechanism underlying the inability as yet to achieve greater effects, is needed in order to follow up on the positive clinical results with improved strategies. This review discusses the experimental results surrounding the current status of our understanding of the mechanism of action of VEGF signaling inhibitors, and the potential for utilizing these agents in the future so that clinical benefits will be measured in years rather than months.