Despite great progress in diagnosis and management of hepatocellular carcinoma (HCC), the exact biology of the tumor remains poorly understood overall limiting the patients' outcome. Detailed analysis and characterization of the molecular mechanisms and subsequently individual prediction of corresponding prognostic traits would revolutionize both diagnosis and treatment of HCC and is the key goal of modern personalized medicine. Over the recent years systematic approaches for the analysis of whole tumor genomes and transcriptomes as well as epigenomes became affordable tools in translational research. This includes simultaneous analyses of thousands of molecular targets using microarray-based technologies as well as next-generation sequencing. Although currently diagnosis and classification of hepatocellular cancers still rely on histological examination of tumor sections, these technologies show great promise to advance the current knowledge of hepatocarcinogenesis, complement diagnostic classification in a setting of microarray-aided pathology, and rationalize the individual drug selection. This review aims to summarize recent progress of system biological approaches in hepatocarcinogenesis and outline potential areas for translational application in a clinical setting. Further, we give an update about known signaling pathways active in HCC, summarize the historical application of whole genomic approaches in liver cancer and indicate ongoing experimental research utilizing novel technologies in diagnosis and treatment of this deadly disease. This will also include the discussion and characterization of new molecular and cellular targets such as Cancer Stem Cells (CSCs).