The neo-angiogenesis process is crucial for solid tumor growth and invasion, as the vasculature provides metabolic support and access to the circulation. Tumor blood vessels differ from normal vessels by altered morphology, blood flow and permeability, and the “switch” of endothelial cells to an angiogenic phenotype is considered a hallmark of the malignant process. Recent evidence indicates that tumor-derived endothelial cells (TEC) possess a distinct and unique phenotype differing from normal endothelial cells at the molecular and functional levels. The anti-angiogenic therapies developed to date are based on tumor endothelial cells being genetically normal. However, it has recently been shown that TEC derived from different tumors are genetically unstable and may acquire resistance to drugs. It has been suggested that TEC may acquire cytogenetic abnormalities within the tumor microenvironment. We found that TEC from different tumors share characteristics in terms of pro-angiogenic properties, survival and resistance to chemotherapy in respect to non-tumor endothelial cells and maintain in vitro an immature pro-angiogenic phenotype in the absence of tumor cells. This was associated with an up-regulation of the AKT/PI3K pathway, involved in the repression of the anti-angiogenic factors thrombospondin-1 and PTEN, and the presence in TEC of the embryonic transcription factor PAX2, responsible for the expression of immature endothelial markers such as NCAM. The in vivo inhibitions of these pathways were shown to display an anti-angiogenic effect on TEC. This review considers the current studies on TEC abnormalities and discusses the hypothesis that at least part of tumor vessels may derive from an intra tumor ongoing embryonic-like vasculogenesis or from tissue endothelial cells switched to angiogenesis from genetic information transmitted from the tumor.