The discovery of PNPLA3 as a genetic risk factor for liver disease has transformed our understanding of the pathogenesis of alcohol-related liver disease (ALD). The recent reclassification of fatty liver disease as steatotic liver disease (SLD), introducing metabolic dysfunction and alcohol-related liver disease (MetALD), has highlighted how genetic and environmental factors synergistically drive liver damage. The PNPLA3 rs738409 variant stands as a paradigmatic example of gene–environment interaction, where its effect on liver disease is dramatically amplified by alcohol consumption, obesity and type 2 diabetes. Understanding these interactions has revealed novel pathogenic mechanisms. The robust genetic evidence and a growing understanding of molecular mechanisms have made PNPLA3 an attractive therapeutic target. Several compounds targeting PNPLA3 are now in clinical development. While initial trials have focused on metabolic dysfunction-associated SLD, the recognition that almost all individuals with excessive alcohol consumption have metabolic comorbidities provides an unprecedented opportunity to evaluate these genetically informed therapies in MetALD. In this review, we examine the role of PNPLA3 in ALD, focusing on gene–environment interactions and therapeutic implications in the context of the new disease classification framework.