Maternal alcohol consumption induces clinical abnormalities of endocrine function and neuroendocrine regulation in both the mother and fetus that may play a role in the etiology of the functional abnormalities observed in Fetal Alcohol Spectrum Disorder (FASD). The major focus of research in our lab is to understand the mechanisms underlying the effects of maternal alcohol consumption on maternal and offspring neuroendocrine function, with a particular emphasis on the hypothalamic-pituitary-adrenal (HPA) axis, a key component of the stress system. Our data demonstrate that alcohol-induced disturbances of the reciprocal interconnections between maternal and fetal/neonatal HPA axes may provide a common pathway for fetal or early programming. We have shown that prenatal exposure to alcohol increases HPA activity in the maternal female and reprograms the fetal HPA axis such that HPA tone is increased throughout life. This is reflected in increased HPA activation and/or delayed or deficient recovery to basal levels following exposure to stressors. Investigation of mechanisms mediating this altered HPA responsiveness has demonstrated that alcohol-exposed animals exhibit HPA dysregulation under basal conditions and following stress, and that differences are further unmasked following perturbations of the system by stress, adrenalectomy and/or receptor blockade. Dysregulation occurs at multiple levels of the axis including the hippocampus, hypothalamus and pituitary, and appears to reflect changes in both HPA drive and corticosterone feedback regulation and/or in the balance between drive and feedback. Although fetal alcohol-exposed animals appear able to initiate compensatory mechanisms to maintain normal basal hormone concentrations under most circumstances, perturbations of the system reveal that tonic or basal HPA tone is in fact increased and likely plays a key role in raising the set point of responsiveness following stress. Furthermore, we have shown that prenatal alcohol exposure appears to have sexually dimorphic effects on HPA regulation, suggesting a role for the gonadal steroids, or possibly an alteration in adrenal-gonadal interactions, in mediating alcohol’s effects on HPA activity and regulation. In this presentation we will present data demonstrating dysregulation of the HPA axis in fetal alcohol-exposed offspring, and discuss potential mechanisms underlying the changes that have been observed. Recent preliminary studies examining effects of prenatal alcohol exposure on the methionine cycle, a metabolic process required for the generation of methyl groups for DNA methylation, and the implications of these effects for alcohol-induced changes in epigenetic regulation of gene expression will also be discussed. Finally, because early life events that produce enhanced reactivity to stress result in elevated cumulative exposure to endogenous glucocorticoids over the lifespan, the implications of our findings for understanding the secondary disabilities that are observed in children with FASD will be explored. Acknowledgements: Supported by grants from NIH/NIAAA (AA07789. AA016683) and the UBC Human Early Learning Partnership.