The use of alcohol has been associated with both an increased risk of acquisition ofHIV‐1 infection and an increased rate of disease progression among those already infected by the virus. The potential for alcohol to exacerbate the effects ofHIVinfection is especially important in thecentral nervous system (CNS)because this area is vulnerable to the combined effects of alcohol andHIVinfection. The effects of alcohol on glial cells are mediated through receptors such as Toll‐like receptor 4 andN‐methyl‐d‐aspartate receptor. This causes the activation of signaling molecules such asinterleukin‐1 receptor‐associated kinaseand various members of the P38 mitogen‐activated protein kinase family and subsequent activation of transcription factors such as nuclear factor‐kappa beta and activator protein 1. The eventual outcome is an increase in pro‐inflammatory cytokine production by glial cells. Alcohol also induces higher levels ofNADPHoxidase in glial cells, which leads to an increased production ofreactive oxygen species (ROS). Viral invasion of theCNSoccurs early after infection, andHIVproteins have also been demonstrated to increase levels of pro‐inflammatory cytokines andROSin glial cells through activation of some of the same pathways activated by alcohol. Both cell culture systems and animal models have demonstrated that concomitant exposure to alcohol andHIV/HIVproteins results in increased levels of expression of pro‐inflammatory cytokines such as interleukin‐1 beta and tumor necrosis factor‐alpha, along with increased levels of oxidative stress. Clinical studies also suggest that alcohol exacerbates theCNSeffects ofHIV‐1 infection. This review focuses on the mechanisms by which alcohol causes increasedCNSdamage inHIV‐1 infection.