After several decades during which little attention was paid to vasopressin and/or urine concentration in clinical practice, interest in vasopressin has renewed with the availability of new, potent, orally active vasopressin-receptor antagonists—the vaptans—and with the results of epidemiological studies evaluating copeptin (a surrogate marker of vasopressin) in large population-based cohorts. Several experimental studies in rats and mice had previously shown that vasopressin, acting via vasopressin V2 antidiuretic receptors, contributes to the progression of chronic kidney disease; in particular, to autosomal dominant polycystic kidney disease. New epidemiological studies now suggest a role for vasopressin in the pathogenesis of diabetes mellitus and metabolic disorders via activation of hepatic V1a and/or pancreatic islet V1b receptors. The first part of this Review describes the adverse effects of vasopressin, as revealed by clinical and experimental studies in kidney diseases, hypertension, diabetes and the metabolic syndrome. The second part provides insights into vasopressin physiology and pathophysiology that may be relevant to the understanding of these adverse effects and that are linked to the excretion of concentrated nitrogen wastes and associated hyperfiltration. Collectively, the studies reviewed here suggest that more attention should be given to the vasopressin–thirst–urine concentration axis in clinical investigations and in patient care. Whether selective blockade of the different vasopressin receptors may provide therapeutic benefits beyond their present indication in hyponatraemia requires new clinical trials.