Genetic tests can help clinicians to diagnose rare monogenic liver diseases. For most common liver diseases, however, multiple gene variants that have small to moderate individual phenotypic effects contribute to the overall risk of disease. An individual's level of risk depends on interactions between environmental factors and a wide range of modifier genes, which are yet to be identified systematically. The latest genome-wide association studies in large cohorts of patients with gallstones, fatty liver disease, viral hepatitis, chronic cholestatic liver diseases or drug-induced liver injury have provided new insights into the pathophysiology of these illnesses and have suggested the contribution of previously unsuspected pathogenic pathways. Studies in mouse models have identified further susceptibility genes for several complex liver diseases. As a result, in the future polygenic risk scores might help to define subgroups of patients at risk of developing liver diseases who would benefit from preventative measures and/or personalized therapy. Now that whole-genome sequencing is possible, comprehensive strategies for integrating genomic data and counseling of patients need to be developed.