Angiogenesis-associated eye diseases are among the most common cause of blindness in the United States and worldwide. Recent advances in the development of angiogenesis-based therapies for treatment of angiogenesis-associated diseases have provided new hope in a wide variety of human diseases ranging from eye diseases to cancer. One group of growth factor receptors critically implicated in angiogenesis is vascular endothelial growth factor receptors (VEGFR), a subfamily of receptor tyrosine kinases (RTKs). VEGFR-1 and VEGFR-2 are closely related receptor tyrosine kinases and have both common and specific ligands. VEGFR-1 is a kinase-impaired RTK and its kinase activity is suppressed by a single amino acid substitution in its kinase domain and by its carboxyl terminus. VEGFR-2 is highly active kinase, stimulates a variety of signaling pathways and broad biological responses in endothelial cells. The mechanisms that govern VEGFR-2 activation, its ability to recruit signaling proteins and to undergo downregulation are highly regulated by phosphorylation activation loop tyrosines and its carboxyl terminus. Despite their differential potentials to undergo tyrosine phosphorylation and kinase activation, both VEGFR-1 and VEGFR-2 are required for normal embryonic development and pathological angiogenesis. VEGFR-1 regulates angiogenesis by mechanisms that involve ligand trapping, receptor homodimerization and heterodimerization. This review highlights recent insights into the mechanism of activation of VEGFR-1 and VEGFR-2, and focuses on the signaling pathways employed by VEGFR-1 and VEGFR-2 that regulate angiogenesis and their therapeutic potentials in angiogenesis-associated diseases.