Lithium is commonly used to treat bipolar disorder, which is associated with altered circadian rhythm. Lithium is a potent inhibitor of glycogen synthase kinase 3 (GSK3), which regulates circadian rhythm in several organisms. In experiments with cultured cells, we show here that GSK3β phosphorylates and stabilizes the orphan nuclear receptor Rev-erbα, a negative component of the circadian clock. Lithium treatment of cells leads to rapid proteasomal degradation of Rev-erbα and activation of clock gene Bmal1. A form of Rev-erbα that is insensitive to lithium interferes with the expression of circadian genes. Control of Rev-erbα protein stability is thus a critical component of the peripheral clock and a biological target of lithium therapy.