Urotensin-II (UII) is an evolutionary conserved peptide which has been initially discovered in the urophysis of the fish goby regulating body fluid composition and vascular tone. Mammalian UII has gained increasing interest since it has been considered as an even more potent vasoconstrictor than endothelin-1 although its efficiency is greatly variable throughout species and vascular beds. UII which mediates its action via binding to the G-protein coupled urotensin-II receptor is also able to stimulate proliferative processes within the vascular wall including smooth muscle cell proliferation and angiogenesis thus making it a potent candidate in mediating disorders associated with vascular remodeling. These responses are mediated by the ability of UII to activate generation of reactive oxygen species (ROS) by the NADPH oxidases NOX2 and NOX4 in vascular cells. Subsequently, this pathway is able to increase activity of hypoxia-inducible factors (HIF) and their transcriptomes, which are importantly involved in vascular proliferative responses. In addition, UII is also able to induce the longevity factor FoxO3a in an NADPH oxidase dependent manner, and this pathway also contributes to angiogenesis and vascular proliferation. Together with studies indicating that UII levels are enhanced in patients with atherosclerosis or pulmonary hypertension, these findings suggest an important function of UII in vascular remodeling and may render UII signalling as an interesting pharmacological target for vascular proliferative disorders.