Targeting tumor vasculature is a therapeutic strategy with great promise in the treatment of many cancers. Clinically, anti-angiogenic reagents that target VEGF/VEGFR2 signaling have met with variable results. Such therapy is predicated on the idea that vascular targets are ubiquitously and homogeneously expressed throughout tumor endothelium. We evaluated the blood vessels in human specimens of brain tumors, malignant melanoma, and colorectal, breast, lung, ovarian, and prostate carcinoma and determined that VEGFR2 is heterogeneously expressed in tumor vasculature in both cancer type and stage specific ways. Using xenografts, anti-angiogenic effect was observed in response to low dose metronomic chemotherapy in melanoma (with higher proportion VEGFR2 positive blood vessels) compared to colorectal carcinoma (with lower proportion VEGFR2 positive blood vessels). This was in the absence of an anti-tumor effect. Evidence also suggested the possible normalization of the treated melanoma tumor blood vessels leading to a decrease in tumor hypoxia.