Over the last 4 years, more than 450 genome-wide association studies (GWAS) have been successfully performed in a variety of human traits, of which approximately 2% relates to the field of hepatology. Whereas the many robust susceptibility gene findings have provided insight into fundamental physiological aspects of the phenotypes that have been studied, the widespread application has also revealed important limitations of the GWAS design. This review aims to systematically summarize both the strengths and the weaknesses of GWAS, as well as underscore important experiences made in model diseases outside the field of hepatology. By reviewing the GWAS performed in hepatology so far on this broader background, extensions and guidelines for the rational application of the study design in hepatology are proposed.