Studies over the past two decades have indicated that protein modifications by acetaldehyde, the first metabolite of ethanol, are generated in the circulation as a result of alcohol abuse and play a major role in the pathogenesis of ethanol-induced diseases. Acetaldehyde can react with nucleophilic groups forming both stable and unstable adducts and several preferred target proteins have already been identified. Protein adducts have been found from the erythrocytes of heavy drinkers and from non-alcoholic volunteers after heavy drinking bouts. Elevated adduct levels also occurred in erythrocytes of women who continued to drink during pregnancy and subsequently gave birth to children with fetal alcohol effects. Evidence of adduct formation has also been observed in plasma proteins, including albumin and lipoproteins. Consequently, there may be interference of cellular functions, breakdown of immune tolerance and induction of autoantibodies towards the resulting neoantigens. Upon ethanol-induced oxidative stress, more abundant amounts and multiple species of adducts may be generated from aldehydic products of lipid peroxidation and through the formation of hybrid adducts. Studies in both human alcoholics and experimental animals have further demonstrated adduct deposition in tissues including the liver, brain, gut, muscle and heart thereby aggravating ethanol toxicity in such organs.