The recognition of lithium as a neurotrophic agent has provided a rationale for evaluation of this agent in animal models of cerebral ischemia. Numerous animal and in vitro studies have shown lithium-mediated neurotrophic effects involve mechanisms highly relevant to the post-stroke population: the induction of brain-derived neurotrophic factor (BDNF) and inhibition of abnormal activity of glycogen synthase kinase 3 (GSK-3). Lithium has consistently been shown to increase serum concentration of the neurotrophic factor, BDNF. BDNF is involved with neuronal proliferation, survival, and differentiation and it facilitates cortical reorganization and functional recovery after focal ischemia (in rats). GSK-3 is a neurotrophic intermediary. In animal and in vitro models, lithium treatment effectively reduces the severity of ischemic damage and protects against ischemic damage of central nervous system (CNS) neurons resulting from glutamate-induced cell death. Importantly, these benefits were present when lithium was given after ischemic events rather than prophylactically.