This review identifies pathways responsible for modulating hepatic protein synthesis following acute and chronic alcohol intoxication and describes mechanism(s) responsible for these changes. Alcohol intoxication induces a defect in global protein synthesis that impairs mRNA translation at the level of peptide-chain initiation. Initiation is regulated at formation of the 43S pre-initiation complex (controlled by eukaryotic initiation factors 2 (eIF2) and eIF2B) and mRNA binding to the 40S ribosome (controlled by eIF4F complex). Alcohol-induced alterations in eIF2 and eIF2B content and activity are best investigated. Ethanol decreases eIF2B activity when ingested acutely or chronically. Reduced eIF2B activity most likely is a consequence of increased eIF2 phosphorylation on Ser⁵¹ following acute intoxication. The increase in eIF2 phosphorylation after chronic alcohol consumption is the same as that induced by acute ethanol intoxication and protein synthesis is not further reduced by long-term alcohol ingestion despite additional reduced expression of initiation and elongation factors. eIF2 phosphorylation appears sufficient to maximally inhibit hepatic protein synthesis. Pretreatment with Salubrinal, which inhibits eIF2(P) phosphatase, before ethanol treatment does not further inhibit protein synthesis or increase eIF2 phosphorylation, suggesting acute ethanol intoxication causes maximal eIF2 phosphorylation elevation and hepatic protein synthesis inhibition. Cessation of ethanol consumption does not rapidly reverse ethanol-induced inhibition of hepatic protein synthesis. Therefore, sustained eIF2 phosphorylation is a hallmark of excessive alcohol intake leading to inhibition of protein synthesis. Enhanced phosphorylation of eIF2 represents a unique response of liver to alcohol intoxication as ethanol-induced elevation of eIF2(P) is not observed in skeletal muscle or heart.