This article discusses some of the mechanisms through which alcohol, delivered pre- or postnatally, alters the activity of the rodent hypothalamic-pituitary-adrenal (HPA) axis. We show that blockade of prostaglandin synthesis, but not opiate receptors, modestly interfered with the HPA axis to acute alcohol injection. Pretreatment with a low dose of alcohol (0.3 g/kg) did not significantly modify the ability of cytokines to stimulate ACTH release in intact rats, but higher doses (>2.0 g/kg) did unless corticosteroid feedback was abolished by adrenalectomy. Animals exposed to an alcohol diet for 7 days showed a significant blunting of their ACTH response to vasopressin and immune signals. This influence was reversed by blockade of nitric oxide with arginine derivatives, suggesting that this gas participates in the inhibitory action of prolonged alcohol on the HPA axis. Finally, adult rats exposed to the drug prenatally showed the expected enhancement of stress-induced ACTH secretion.