Thirty-five years ago Charles Lieber and colleagues (1975) published a seminal article in liver research, showing that alcohol itself is the primary cause for the higher prevalence of liver disease seen in alcoholic patients and not dietary deficiencies and malnutrition that often accompany alcoholism. Their groundbreaking research dispelled previously held theories that alcohol was not a major cause of liver damage and led to several decades of study of the deleterious effects of alcohol and its metabolism on the liver. Since that early study, clinical and experimental studies have continued to show a firm connection between high amounts of alcohol consumption and liver disease. This article tracks advances in alcohol-related liver disease research over the past 40 years and describes how these discoveries are helping scientists to gain insight into therapeutic targets that may help to combat this life-threatening disease.