The brain is one of the major target organs of ethanol actions, and its chronic and acute intoxication results in significant alterations in brain structure and function, and in some cases to neurodegeneration. Glial cells and Toll-like receptors (TLRs) are vital players in CNS immune response; dysregulation of this response plays an important role in brain damage and neurodegeneration. Ethanol has immunomodulatory effects and induces specific alterations in the TLRs response in many tissues. These actions depend on the cell type, ethanol dose and treatment duration, as well as the concomitant presence of pathogens and their characteristics. Recent findings indicate that low concentrations of ethanol (10 mM) promote inflammatory processes in brain and in glial cells by up-regulating cytokines and inflammatory mediators (iNOS, NO, COX-2), and by activating signaling pathways (IKK, MAPKs) and transcriptional factors (NF-kappaB, AP-1) implicated in inflammatory injury. TLR4/IL-1RI receptors may be involved in ethanol-mediated inflammatory signaling, since blocking these receptors abolishes the production of ethanol-induced inflammatory mediators and cell death. We propose that at low physiologically relevant concentrations, ethanol facilitates TLR4/IL-1RI recruitment into lipid rafts microdomains, leading to the activation and signaling of these receptors. In summary, current results suggest that TLR4/ IL-1RI are important targets of ethanol-induced inflammatory brain damage.