Proper vascular regulation is of paramount importance for the control of blood flow to tissues. In particular, the regulation of peripheral resistance arteries is essential for several physiological processes, including control of blood pressure, thermoregulation, and increase of blood flow to central nervous system (CNS) and heart under stress conditions such as hypoxia. Arterial tone is regulated by the periarterial autonomic nervous plexus, as well as by endothelium-dependent, myogenic and humoral mechanisms. Underscoring the importance of proper vascular regulation, defects in these processes can lead to diseases such as hypertension, orthostatic hypotension, Raynaud's phenomenon, defective thermoregulation, hand-foot syndrome, migraine and congestive heart failure. Here, we review the molecular mechanisms controlling the development of the periarterial nerve plexus, retrograde and localized signaling at neuro-effector junctions, the molecular and cellular mechanisms of vascular regulation, and adult plasticity and maintenance of periarterial innervation. We particularly highlight a newly discovered role for vascular endothelial growth factor (VEGF) in the structural and functional maintenance of arterial neuro-effector junctions. Finally, we discuss how defects in neuronal vascular regulation can lead to disease.