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The vascular endothelial growth factor (VEGF)/VEGF receptor system plays a central regulatory role in physiological and pathological angiogenesis. During embryogenesis, the VEGF/VEGF receptor system is critically involved in the formation of the vascular system by regulating both the growth and the survival of blood vessels. In the vasculature of the adult organism, the high-affinity signaling VEGF receptor-2 (VEGFR-2) is downregulated but is reinduced during transient phases of physiological angiogenesis. Moreover, a variety of pathological conditions are associated with the upregulation of VEGF and the VEGF receptors. VEGF stimulates angiogenesis and the survival of endothelial cells in tumors, thereby enabling tumor expansion and metastasis. VEGF is also upregulated in ischemic diseases, such as coronary heart disease or stroke, and is thought to stimulate the—often insufficient—compensatory formation of blood vessels. The implication of VEGF in these pathological processes has opened up promising new therapeutic strategies. In malignancies, attempts are made to inhibit VEGF-mediated signaling and angiogenesis. In ischemic disease, the exogenous application of VEGF may enhance the formation of collaterals. However, considering the complexity of the regulatory pathways involved in the formation of new blood vessels under physiological conditions, a treatment relying on VEGF as the sole angiogenic factor may be insufficient, and the combination with other factors may improve the functionality of newly formed blood vessels and the efficacy of therapeutic angiogenesis.