Physicians have recognized for more than a century that alcohol use is associated with infections and that alcoholics are especially at risk for pneumonia. Clear evidence now indicates that alcohol has a systemic effect on every organ. This review first presents a clinical case to describe a patient with immunity issues complicated by alcohol use-a setting familiar to many clinicians. This is followed by a description of the molecular mechanisms that explain the secondary immune deficiency produced by alcohol in the host, focusing mostly on the gut and lower respiratory mucosal immunity. The goal of this review is to increase awareness of the new mechanisms being investigated to understand how alcohol affects the human immune system and the development of new strategies to attenuate adverse outcomes in the affected population.