Tumor blood vessels play an important role in tumor progression and metastasis. Thus, targeting tumor blood vessels is an important strategy for cancer therapy, especially for head and neck cancer patients. Tumor blood vessels generally sprout from pre-existing vessels and have been thought to be genetically normal. However, tumor blood vessels have been shown to differ from their normal counterparts, for example, by changes in morphology. The authors isolated tumor endothelial cells (TECs) from mouse tumor xenografts and have shown that the TECs are abnormal. TECs up-regulate many genes and proliferate more rapidly and migrate more than normal endothelial cells (NECs). Furthermore, TECs were found to be cytogenetically abnormal. We conclude that TECs can acquire cytogenetic abnormalities while in a tumor microenvironment.To develop ideal antiangiogenic therapies, understanding the crosstalk between blood vessels and the tumor microenvironment is important.Here, we provide an overview of the current studies on TEC abnormalities and a discussion about possible mechanisms for how tumor the microenvironment makes TECs abnormal.