Chronic ethanol feeding sensitizes Kupffer cells to activation by lipopolysaccharide (LPS), leading to increased production of tumor necrosis factor α (TNFα). The regulation of TNFα synthesis is controlled by both transcriptional and post-transcriptional mechanisms via the integration of complex signal transduction pathways activated in response to LPS exposure. Recent data has shown that increased LPS-stimulated phosphorylation of extracellular signal-regulated kinase pathway 1/2 (ERK1/2) is one of the important molecular targets of chronic ethanol in Kupffer cells. This increased activation of ERK1/2 after chronic ethanol is associated with increased expression of Egr-1, a transcription factor required for enhanced LPS-stimulated TNFα mRNA expression after chronic ethanol exposure. egr-1 null mice are protected from the development of fatty liver injury in response to chronic ethanol feeding, identifying an essential role for Egr-1 in the development of chronic ethanol-induced liver injury. Here we review recent studies aimed at understanding the mechanisms by which chronic ethanol enhances the LPS→ERK1/2→Egr-1→ΤNFα pathway in Kupffer cells. These studies identify a critical role for nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived reactive oxygen species in the activation of ERK1/2 and subsequent production of TNFα in Kupffer cells after chronic ethanol feeding.