Alcohol exerts potent suppressive effects on the immune system that significantly increase host susceptibility to a variety of infections, particularly pneumonia. Historically, tuberculosis has been strongly associated with alcohol abuse. Although the relationship between alcohol abuse and tuberculosis is widely appreciated, the basic mechanisms by which alcohol immunosuppresses the host remain to be clarified. A major obstacle in furthering our understanding of this association has been the difficulty in distinguishing between the effects of alcohol per se and the other frequent sequelae of alcoholism such as nutritional deficiencies, liver disease, cigarette smoking, hygienic factors, and lifestyle. This article focuses on the role of tumor necrosis factor-alpha (TNF) in host defense and how alcohol modulates the activity of this important cytokine. While TNF's role in mediating the lethal consequences of infection has been the subject of much conjecture, this review focuses on the emerging evidence that TNF is an essential factor in the normal immune response to numerous infections, including tuberculosis.