There are now more than 10 million cancer survivors in the United States. With these numbers, chronic sequelae that result from cancer therapy have become a major health care problem. Although radiation therapy of the brain has improved cancer cure rates, learning disorders and memory deficits are a common consequence of this therapy. Here we show that glycogen synthase kinase 3β (GSK-3β) is required for radiation-induced hippocampal neuronal apoptosis and subsequent neurocognitive decline. Inhibition of GSK-3β either by small molecules (SB216763 or SB415286) or by ectopic expression of kinase-inactive GSK-3β before irradiation significantly attenuated radiation-induced apoptosis in hippocampal neurons. GSK-3β inhibition with SB216763 or SB415286 also decreased apoptosis in the subgranular zone of the hippocampus in irradiated mice, leading to improved cognitive function in irradiated animals. Studies of the molecular mechanisms of the cytoprotective effect showed that GSK-3β activity in hippocampal neurons was not significantly altered by radiation, pointing to the indirect involvement of this enzyme in radiation-induced apoptosis. At the same time, radiation led to increased accumulation of p53, whereas inhibition of the basal level of GSK-3β activity before radiation prevented p53 accumulation, suggesting a possible mechanism of cytoprotection by GSK-3β inhibitors. These findings identify GSK-3β signaling as a key regulator of radiation-induced damage in hippocampal neurons and suggest that GSK-3β inhibitors may have a therapeutic role in protecting both pediatric and adult cancer patients and may help to improve quality of life in cancer survivors. [Cancer Res 2008;68(14):5859–68]