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The management of hepatocellular carcinoma (HCC) has substantially changed in the past few decades. Improvements in patient stratification (for example, using the Barcelona Clinic Liver Cancer staging system) and the introduction of novel therapies (such as sorafenib) have improved patient survival. Nevertheless, HCC remains the third most common cause of cancer-related deaths worldwide. Decision-making largely relies on evidence-based criteria, as depicted in the US and European clinical practice guidelines, which endorse five therapeutic recommendations: resection; transplantation; radiofrequency ablation; chemoembolization; and sorafenib. However, areas still exist in which uncertainty precludes a strong recommendation, such as the role of adjuvant therapies after resection, radioembolization with yttrium-90 or second-line therapies for advanced HCC. Many clinical trials that are currently ongoing aim to answer these questions. The first reported studies, however, failed to identify novel therapeutic alternatives (that is, sunitinib, erlotinib or brivanib). Moreover, genomic profiling has enabled patient classification on the basis of molecular parameters, and has facilitated the development of new effective drugs. However, no oncogene addiction loops have been identified so far, as has been the case with other cancers such as melanoma, lung or breast cancer. Efforts that focus on the implementation of personalized medicine approaches in HCC will probably dominate research in the next decade.