Hepatocellular carcinoma (HCC) is the leading cause of primary liver cancers. Surveillance of individuals at specific risk of developing HCC, early diagnostic markers, and new therapeutic approaches are essential to obtain a reduction in disease-related mortality. In the last decades imaging technologies, statistical models, and standardized diagnostic procedures associated with clinical guidelines for intervention significantly enhanced the success rate and life expectancy of HCC patients. In addition, the work of several research laboratories contributed to the identification of markers and pathways altered in HCC which represent potential biomarkers or molecular targets for therapy. In this short review we describe the current approaches for HCC diagnosis and treatment and the most recent advancements in the characterization of biomolecular mechanisms implicated in the pathogenesis and progression of HCC.