X-linked nephrogenic diabetes insipidus (XNDI) is a severe congenital kidney disease caused by mutations in the V2R gene. Currently, there is no effective drug to specifically treat XNDI, mainly because there are no good animal models of the disease. However, Jürgen Wess and colleagues, at the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, have now developed a viable mouse model of XNDI that recapitulates the major manifestations of the human disease. As analysis of the mouse model indicated that disease was associated with increased expression in the kidney of the protein EP4, the authors tested selective EP4 receptor agonists as potential therapeutics, and found that they alleviated all the symptoms of disease. The authors therefore suggest that selective EP4 receptor agonists could be of benefit to individuals with XNDI and hope that their mouse model can be used to test additional new therapeutic strategies.