The expression of angiogenic factors in tumors is controlled by intrinsic factors in the tumor and by the host microenvironment. Endothelial cells within particular tumor microenvironments interact not only with tumor cells but also with immune cells, fibroblasts, pericytes, and the extracellular matrix (ECM). The relationship and cross-talk among these cells determine gene expression, phenotypic distinction, and ultimately whether endothelial cells survive, proliferate, or undergo apoptosis. The diversity of angiogenic factor expression in tumors at different sites, combined with the fact that endothelial cells in different organs and tumors are phenotypically distinct, constitutes a formidable challenge for the development of effective anti-angiogenic therapies.