Identification of novel oncogenes and tumor suppressors in hepatocellular carcinoma (HCC) is challenging, both because of the tumor complexity and the difficulty in integrating the very large amount of data provided by different approaches. The authors consider it very important to identify new pathways of carcinogenesis and to understand the mechanisms underlying their alteration in tumors to design personalized treatments for HCC. In this review, the main global genomic approaches are considered in detail. The authors present a catalog of the most important oncogenes and tumor suppressor genes that have been found to be mutated in HCC and hepatocellular adenoma. They also review the results provided by transcriptome and miRNA profiling, in terms of molecular tumor classification. The authors anticipate that high-throughput sequencing will considerably refine the description of the genetic alterations in HCC. They also predict that systems biology, the recently developed interdisciplinary research field, will be very important to integrate the colossal amounts of data generated by the new technologies and to identify useful clinical applications.