International Journal of Cell Biology the mitochondrial-based apoptotic machinery to allow the cells to escape potentially lethal damage. There have been attempts to exploit these pro-survival roles in neurode- generative diseases, which are typiﬁed by high apoptosis rates. Reduction of disease-associated apoptosis by GSK-3β modulating agents can restore balance to oﬀ-kilter apoptotic machinery, resulting in decreased cellular turnover and the resultant protection of the at-risk neuronal population. In addition to diabetes, and neurodegenerative disorders, we believe that GSK-3β inhibition may play a promising role in patients receiving irradiation. While radiation dose-escalation has been important for the treatment of multiple cranial tumors (e.g., brain metastases, primary gliomas) and benign disorders (e.g., vestibular schwannoma, meningioma), the treatment is limited by the eﬀects of irradiation on healthy surrounding neurons. It has been demonstrated that GSK-3β inhibition can protect hippocampal neurons (in primary culture and murine pups) from irradiation-induced damage [9, 70]. Thotala et al. demonstrated improved survival of intestinal crypt cells and increased latency to murine GI-related death from irradiation [77]. This report suggested that GSK- 3β inhibitors could reduce deleterious consequences of intestinal irradiation and possibly improve patient quality of life measures. It would be worthwhile to explore their utility in syngenic murine models of neural cancer, murine tumor xenografts, as well as human clinical trials of patients in the setting of re-irradiation (e.g., recurrent glioma). Reports of radiation protection have also been demonstrated with small molecular inhibitors of GSK-3β in the gastrointestinal system. In cancer, however, the apoptotic machinery is often defective allowing cells to undergo unregulated proliferation. In this case, negative regulation of GSK-3β can serve to tip the balance in favor of apoptosis. Dickey et al. demonstrated the ability of GSK-3β inhibition to eﬀectively enhance cell death of neuroblastoma cells in vitro and in a murine xenograft model [79]. Similar ﬁndings have been demon- strated in glioma [81, 82]. The interplay between GSK-3β regulation and other cell death stimuli is being carefully studied across a wide variety of cancer types, and there is promising data suggesting a strong role for this form of ther- apy in the near future. The bifunctional role of GSK-3β as a facilitator of apoptosis and a mediator of pro-survival signals has important implications in both the generation of novel therapies and the understanding of complex disease states. The use of both positive and negative regulators of GSK- 3β oﬀers exciting treatment possibilities for a multitude of diseases. 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