Lithium, the lightest metal, with an atomic number of 3, was formally introduced into medicine in 1949, when John Cade discovered the therapeutic effects of lithium carbonate on bipolar disorder. Since then, lithium has become one of the most effective and widely prescribed drugs for mood stabilization in the treatment of psychiatric disorders. 1 Recent studies in both experimental and clinical settings have further revealed the potential of lithium as a neurotrophic and neuroprotective agent for the treatment of acute brain injury (e.g., stroke or ischemia), as well as chronic neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. Multiple signaling pathways and molecular and cellular targets have been identified to account for lithium’s neurologic effects.2 In addition, lithium has been shown to modulate several aspects of hematopoiesis, such as enhancing the production and release of G-CSF, improving the quantity and quality of neutrophil, increasing monocyte differentiation and activity, and assisting in hematopoietic stem cell mobilization in bone marrow transplantation. 3 The clearance of lithium depends exclusively on renal excretion, and, as people age, the ability of lithium clearance decreases. Interestingly, after glomerular filtration, 80% of the filteredlithiumisreabsorbedviarenaltubules.Becauseof its unique interactions with kidney cells, lithium has been an important and versatile tool for understanding renal physiology and pathophysiology. 4 In medicine, despite its usefulness in psychiatric and neurologic disorders, lithium is knowntohaveadverse effects inkidneys, which, notsurprisingly, depend on the dose and duration of use, patient age and health status, and the presence of concurrent medications. 5 The notable adverse effects of lithium include acute lithium toxicity, CKD, and nephrogenic diabetes insipidus (NDI), which are especially common in persons with longterm use and in elderly patients.5 In stark contrast, if used briefly and at low doses, lithium can be renoprotective. In this regard, recent studies have shown the protective effects of lithium in experimental models of AKI induced by renal ischemia-reperfusion, 6,7 nephrotoxin, 8 and endotoxin. 9 In this issue of JASN ,B aoet al. report that a single dose of lithium given after AKI promotes the recovery and repair of kidneys, whereas de Groot and colleagues show that lithium induces G2 cell cycle arrest in the principal cells of the collecting ducts, which may contribute to the development of NDI. 10,11