Background. Fetal alcohol spectrum disorders (FASD) are associated with hypoplasia and impaired neuronal migration in the cerebellum. Previous studies linked cerebellar hypoplasia in FASD to inhibition of insulin and insulin-like growth factor (IGF) signaling. Since aspartyl (asparaginyl)-β-hydroxylase (AAH), a mediator of neuronal motility, is stimulated by insulin and IGF's, we examined the potential role of reduced AAH expression as a mediator of ethanol impaired neuronal migration. Methods. Effects of ethanol on IGF-I stimulated AAH expression and neuronal migration were examined in human PNET2 cerebellar-derived neuronal cells. We also examined the role of increased glycogen synthase kinase 3 (GSK) activation in relation to AAH protein expression and motility in ethanol-exposed PNET2 cells. Results. Ethanol significantly reduced IGF-I stimulated AAH protein expression and directional motility without significantly reducing AAH mRNA levels. Further studies demonstrated that: (1) AAH protein could be phosphorylated by GSK-3β; (2) AAH protein expression was decreased by high levels of GSK-3β activity; (3) AAH protein was increased by inhibition of GSK-3β, caspase, and/or protease activities; and (4) ethanol-impaired AAH protein expression and motility could be partially rescued by chemical inhibition of GSK-3 and caspase activity. Conclusions. Ethanol-impaired neuronal migration is mediated by inhibition of IGF-I stimulated AAH expression due to increased GSK-3 phosphorylation and proteolytic (caspase) degradation of AAH protein. Therapeutic strategies to reduce CNS developmental abnormalities in FASD should target impaired neuronal responsiveness to IGF's and/or the increased levels of oxidative stress leading to over-activation of caspases.