Angiogenesis is a very important process not only in embryogenesis but also in a variety of severe diseases such as cancer and diabetes. Recently, molecular mechanism of angiogenesis has been extensively studied, and several signaling systems were found to be involved in this process. Among these, VEGF (vascular endothelial growth factor) family and its receptors (VEGFR-1, -2 and-3) regulate the earliest step of blood vessel formation in embryogenesis. VEGFR-2 (KDR/Flk-1) minus mice lack both blood vessel formation and hematopoiesis and die at E 8.5. VEGFR-1 (Fit-1) minus mice are also lethal at a similar stage due to vascular dysorganization. VEGFR-3 functions at the middle stage of angiogenesis and lymphangiogenesis. On the other hand, Angiopoietin-Tie system and Ephrin-Eph system are involved in the interrelationship between endothelial cell and smooth muscle cell and the differentiation of arterial and venous endothelial cell, respectively. Thus, highly organized signaling systems are required for physiological angiogenesis. In the pathological processes such as tumor angiogenesis, VEGF appears to play a central role in new blood vessel formation. To regenerate the blood vessels, stimulation of VEGF-VEGF receptor system seems most effective, and VEGF-A and VEGF-E may be useful tools since they stimulate most potent signal transducer, VEGFR-2.