The interest in dissecting the genetic and environmental components of complex human disease is growing, fueled by the emerging advances in the field of genomics and related disciplines. Improved understanding of the pathogenesis of complex liver diseases such as gallbladder stones, nonalcoholic fatty liver disease, viral hepatitis, and hepatocellular carcinoma remains a goal of the clinical and experimental hepatologist alike. Despite the scientific progress and technological advancement, elucidating the underlying mechanisms of complex hepatic diseases from the genomic standpoint will be demanding. Complexity of genomic structure and function, disease heterogeneity, influence of the environment on disease development and progression, and epigenetics all contribute to the challenge. To overcome these obstacles, novel conceptual frameworks regarding biological systems and human diseases are necessary in addition to a coordinated endeavor among different scientific disciplines. Deciphering in an integrated fashion the genomic, transcriptional, and translational aspects of the pathogenesis of complex liver diseases will lead to their better prediction, diagnostics, and treatment.