Blood vessels affect the quality of life in many ways. They provide an essential nutritive function during growth and repair of tissues but, on the other hand, can become affected by disorders or trauma, resulting in bleeding, thrombosis, arterial stenosis, and atherosclerosis. Three molecular systems, the vascular endothelial growth factor (VEGF) system, the plasminogen system, and the coagulation system, have been implicated in the formation and pathobiology of blood vessels. This review focuses on the role of these systems in these processes. Recent gene-targeting studies have identified VEGF as a potent modulator of the formation of endothelial cell-lined channels. Somewhat unanticipated, the initiator of coagulation is not only involved in the control of hemostasis but also in the maturation of a muscular wall around the endothelium. With different murine models of cardiovascular disease, a pleiotropic role of the plasminogen system was elucidated in thrombosis, in arterial neointima formation after vascular wound healing and allograft transplantation, in atherosclerosis, and in the formation of atherosclerotic aneurysms. Surprisingly, tissue-type plasminogen activator is also involved in brain damage after ischemic or neurotoxic insults. The insights from these gene-targeting studies have formed the basis for designing gene therapy strategies for restenosis and thrombosis, which have been successfully tested in these knockout models.