Lithium (Li⁺) is used to treat affective disorders. Prolonged use in adults results in polyuria and ultimately renal fibrosis. Early in life, kidney maldevelopment has been described (Christensen et al. 1982). In kidney, Li⁺ inhibits Glycogen Synthase Kinase-3b (GSK-3b) by increased phosphorylation on serine9 (s9) (Rao et al. 2005). In the present study we hypothesized that Li⁺ leads to damage of the developing kidney through inhibition of GSK-3b. We studied the expression of GSK-3b in the developing rat and human kidney and the phosphorylation state during postnatal development and after Li⁺ treatment. Li⁺ was given through the chow (50 mmol Li⁺/ kg chow) to female Wistar rats with litters reduced to 8 pups, in the postnatal (P) days P0-P14 or P7- P30. Pups were sacrificed and kidney tissue was collected for molecular analysis or perfusion fixed for immunohistochemistry. At P30, Li⁺- treated rat pups were polyuric and the kidneys exhibit dilated pelvis with medullary atrophy. During postnatal kidney development, GSK-3b mRNA was stably expressed in kidney cortex and medulla, whereas GSK-3b and pGSK-3b-s9 protein abundances decreased significantly (at P28: 10 and 15 % of levels at P0, P<0.0001, n=6). Li⁺- treatment increased pGSK-3b-s9 significantly whereas total GSK-3b expression was unaltered. Immunohistochemical analysis for GSK-3b and pGSK- 3b-s9 showed labeling associated primarily with the entire collecting duct system both in adult and fetal human kidney and postnatal rat kidney. In conclusion, Li⁺ leads to kidney damage in the postnatal period and inhibits GSK-3b in renal tissue. GSK-3b activity could be necessary for proper kidney development. Christensen, S., Ottosen, P.D. & Olsen, S. 1982. Acta Pathol Microbiol Immunol Scand [A] 90, 257–267. Rao, R., Zhang, M.Z., Zhao, M., Cai, H., Harris, R.C., Breyer, M.D. & Hao, C.M. 2005. Am J Physiol Renal Physiol 288, F642-F649.