Angiogenesis is an important component of the process of atherosclerosis. It has recently been demonstrated that VEGF, a potent angiogenic growth factor, increases the rate of atherosclerosis in animal models. There is a significant body of literature concerned with the ability of polyphenols to alter VEGF signaling and angiogenesis. However, the potential for polyphenols to influence atherosclerosis as a result of inhibiting VEGF signaling and VEGF-dependent angiogenesis has not been considered. This chapter summarizes and reviews the existing literature concerning the effects of polyphenols on VEGF signaling, angiogenesis, and atherosclerosis. The data suggest that some polyphenols can inhibit VEGF signaling, as well as angiogenesis and atherosclerosis, via a variety of mechanisms and, in some cases, at physiologically relevant concentrations. However, there is a lack of published data from studies with polyphenol metabolites, and the majority of reports are from studies using aglycones at supraphysiological concentrations. Data from epidemiological studies show there is a positive correlation between polyphenol consumption and reduced risk of cardiovascular disease, but the role of specific compounds is difficult to determine from these. Future research should focus on establishing whether or not the reported antiatherosclerotic effects of polyphenol-rich foods and extracts are due to the polyphenols inhibiting VEGF signaling. Further research is required to elucidate the influence of bioavailability, metabolism, and combinations of polyphenols found in foods on VEGF signaling.