Sorafenib (Nexavar®, Bayer), a multi-targeted tyrosine kinase inhibitor, was the first systemic agent that demonstrated a significant improvement in the overall survival in patients with advanced hepatocellular carcinoma and well-preserved liver function. This drug is now recommended in patients with advanced hepatocellular carcinoma as first-line therapy and for patients not suitable for locoregional treatment. This brief article, produced by a multidisciplinary panel including specialists in gastroenterology and oncology, provides an overview of the major issues related to systemic treatment of hepatocellular carcinoma with sorafenib, including staging and prognostic strategies, assessment of liver disease and its complications, and efficacy and safety of this molecule. Particular emphasis is given on how to improve tolerability of sorafenib in difficult-to-treat patients.