The role of alcohol consumption and alcoholism as an addiction in regulating the chemistry of the brain and its physiology has gained a backlog of interest over the past few decades. Besides the notion that alcohol acts as a brain depressant, the molecular mechanisms and neuronal interactions are not well understood. Emerging evidence implicates alcohol as a neurochemical messenger that influences a cross talk amongst the nervous, immune, and endocrine systems. Specifically, alcohol acts as a crucial regulator of the hypothalamic-pituitary-adrenal (HPA) axis, thereby modulating the release of hormones, particularly adrenocorticotropic hormone (ACTH) and corticosterone (CORT). It is the aim of this review, therefore, to investigate current concepts on how alcohol, particularly ethanol, and alcoholism affect neuro-immune-endocrine neurochemical interactions via the regulation of the HPA axis, taking into consideration bio-behavioral and physiochemical aspects. (C) 2004 Published by Elsevier Inc.