Lithium is widely used to treat bipolar disorder, but its mechanism of action in this disorder is unknown. Several molecular targets of lithium have been identified, but these putative targets have not been shown to be responsible for the behavioral effects of lithium in vivo. A robust model for the effects of chronic lithium on behavior in mice would greatly facilitate the characterization of lithium action. We describe behaviors in mice that are robustly affected by chronic lithium. Remarkably, these lithium-sensitive behaviors are also observed in mice lacking one copy of the gene encoding glycogen synthase kinase-3␤ (Gsk-3␤), a well established direct target of lithium. In addition, chronic lithium induces molecular changes consistent with inhibition of GSK-3 within regions of the brain that are paralleled in Gsk-3␤ ϩ/Ϫ heterozygous mice. We also show that lithium therapy activates Wnt signaling in vivo, as measured by increased Wntdependent gene expression in the amygdala, hippocampus, and hypothalamus. These observations support a central role for GSK-3␤ in mediating behavioral responses to lithium.