Urotensin II (U-II) is a cyclic peptide isolated from a fish. Subsequently, human U-II and its receptor were identified. In rat thoracic aorta U-II triggers powerful vasoconstrictor activity. However, the constrictor response to U-II appears to be variable and highly dependent on the vascular bed examined. Vasoconstriction is not its only effect; U-II and its receptor have been demonstrated in the central nervous system, where U-II induces a cardiovascular, behavioural, motor and endocrine response and in the kidney, where it seems to influence renal hemodynamics but also salt and water excretion, in rat pancreas where it inhibits insulin secretion, in the heart where it seems to play a role in cardiac hypertrophy and fibrosis. In humans high plasma or urine levels of U-II have been described in some pathologic conditions. Peptidic and non peptidic UT receptor antagonists have been synthesized and their effects have been evaluated particularly in animal models of diabetes and heart failure. After promising results in animal models, palosuran, a non peptidic U-II antagonist has been administered also in diabetic patients to evaluate its potential nephroprotective activity. This review presents the data available on the U-II system and its role in physiological and pathological conditions, together with data regarding palosuran and other non peptidic and peptidic U-II antagonists.