The period from 1959 to 1974 marked a shift toward understanding alcohol-related liver disease as a multifactorial process, driven by multiple metabolic and histopathological pathways rather than a single cause. The identification of the microsomal ethanol-oxidizing system in 1970 revealed a second, NADPH-dependent, oxygen-requiring route of ethanol metabolism that helped explain tolerance, drug interactions, and the induction of metabolic pathways with chronic exposure. Concurrently, evolving histopathology linked vascular and hepatocellular injury with clinical manifestations, culminating in a recognizable pattern described as sclerosing hyaline necrosis of the liver in alcoholic disease. Experimental work, including primate models and human volunteer studies showing direct hepatic effects of isocaloric alcohol substitution, underscored a spectrum of liver injury that spans steatosis to hepatitis and cirrhosis. Therapeutic exploration, exemplified by corticosteroid trials in severe alcoholic hepatitis, highlighted patient selection and treatment limitations, shaping later guidelines and research priorities. Collectively, these efforts moved the field toward a cohesive, mechanistic framework for alcohol-related liver disease that accommodated diverse etiologies and disease stages.