It is now well established that angiogenesis is an obligatory event for the growth and progression of solid tumors beyond the size limit (approximately 2 mm diameter) imposed by simple diffusion for the nutrient supply. Human tumors can remain dormant for years owing to a balance between cell proliferation and apoptosis. Several hypotheses have been articulated regarding the critical importance of tumor angiogenesis in the development and metastatic spread of tumors, and how preventive/therapeutic inhibition of angiogenesis might be exploited as a novel means of controlling cancer growth. Anti-angiogenic therapy is suggested as one of the most promising approaches to control cancer, as endothelial cells are generally non-transformed cells and are less prone to acquire drug resistance. Tumor vasculature could be an important prognostic marker, and an independent predictor of pathologic stages and malignant potential of cancer. This review is focused on recent developments and comprehensive mechanistic aspects of phytochemicals related to an interplay of angiogenic promoters and inhibitors, and associated signaling in both tumor as well as endothelial cells. Since, vascular endothelial cells constitute the first line exposure to the blood-borne agents, it is plausible that anti-angiogenic activity of phytochemicals could be associated with lowering the risk of cancer by preventing the growth and metastasis of tumor.