Angiogenesis promotes tumor growth and metastasis. Current paradigms that attempt to define its contribution to tumorigenesis include the concept of the angiogenic switch and the role of circulating endothelial progenitor cells. Specific metabolic signaling pathways that respond to oxygen and nutrients in the tumor microenvironment are also critical effectors of the angiogenic response. These pathways may be exploited for therapeutic benefit to deliver agents at the appropriate dose and time (metronomic therapy), to promote vessel normalization and prevent vascular expansion, and to improve drug delivery and reduce drug resistance. The angiogenic switch is associated with loss of tumor dormancy and is regulated by transcription factors that activate specific target genes. These transcription factors and transcriptional activators/ repressors respond to nutrients and oxygen to regulate the vascular endothelial cell phenotype. Glucose metabolism and specific signaling pathways regulate the expression of several angiogenic and anti-angiogenic transcription factors including p53, Id, PPAR, Hif1α, c-myc, Foxo, and RUNX2 as well as several cofactors such as PGC1α and SIRT. Conversely, these transcriptional regulators also alter the overall signaling pathways in activated endothelial cells and modify the metabolic state of vascular cells. This review will focus on how the RUNX2 and PGC1α transcriptional regulators respond to nutrients such as glucose and how they affect the metabolic state of endothelial cells. The feasibility of using these transcription factors as markers of the angiogenic phenotype and as targets for chemoprevention and/or treatment is discussed.